Ivory Coast and Ghana launch campaigns for their fourth consecutive World Cup appearances with away fixtures this week against much lower-ranked opponents Liberia and Comoros respectively.
It is a feat only Cameroon have achieved among the 54 African football nations, qualifying for the 1990, 1994, 1998 and 2002 tournaments before a saved penalty cost them a 2006 place.
Reigning African champions Ivory Coast travel to Liberia - the country that produced 1995 World and European Footballer of the Year George Weah - who are 64 places lower in the global rankings.
Ghana visit the Comoros, an island state off the south-east coast of Africa and 147 rungs lower than their opponents on the Fifa list.
Seeding means many of the 20 second-round qualifiers, to be played on a home-and-away basis between Wednesday and next Tuesday, appear mismatched.
Algeria are 109 places above Tanzania, Cape Verde 93 rungs higher than Kenya, and Egypt and Senegal 79 places each above Chad and Madagascar respectively.
However, a glimmer of hope for lower-ranked nations is that they enjoy home advantage first, offering a chance to build a lead in ties to be decided by goal aggregate.
Manchester City midfielder Yaya Toure, who hopes to win a record-extending fifth consecutive African Footballer of the Year title in January, is a notable Ivorian absentee.
France-born coach Michel Dussuyer said the 32-year-old "has not expressed a desire to rejoin the squad".
Toure was a key figure as the Elephants finally fulfilled a decade of promise by winning the Africa Cup of Nations last February in Equatorial Guinea.
But he has resisted the physical exertions of travelling to and from Africa since, missing the start of the Nations Cup defence, a drab 0-0 draw away to Sierra Leone.
Ivory Coast will also be without Strikers Wilfried Bony, Salomon Kalou and Thomas Toure.
Dussuyer has called up Roger Assale as backup with defender Arthur Boka, goalkeeper Ali Badra Sangare and midfielder Serge Yao N'Guessan also returning.
While Ivory Coast, who replaced Algeria at the top of the African rankings last week, had a first-round bye, Liberia took an unusual route past Guinea-Bissau.
Held 1-1 at home, the Lone Stars triumphed 3-1 away and all four of their goals in the tie came from Portugal-based William Jebor, who is on loan to a Spanish second division outfit.
"Liberia are a respectable side who beat Tunisia in a 2017 Cup of Nations qualifier," warned Dussuyer. "We are expecting a difficult confrontation."
Ghana will also lack a star midfielder as injury rules out Kwadwo Asamoah from 2015 European Champions League runners-up Juventus.
But two vital Black Stars components - midfielder Andre Ayew and striker Asamoah Gyan - are back after missing a friendly draw with Canada in Washington.
Gyan was chosen by coach Avram Grant, the former Chelsea and West Ham United manager, after a two-month battle with a knee injury.
"It has been frustrating as I regain fitness only to suffer a setback and have to start all over again," said the China-based 29-year-old.
Comoros, with a squad including footballers who play in the amateur fourth and fifth levels of French club football, secured a date with Ghana on away goals after drawing twice with Lesotho.
Teenage English Premier League reserves Kelechi Iheanacho of Manchester City and Alex Iwobi of Arsenal have been called up by Nigeria for the trip to Swaziland.
Super Eagles coach Sunday Oliseh, who said he was "shocked" by the recent retirement of Emmanuel Emenike, recalled veteran USA-based striker Obafemi Martins.
South Africa, away to Angola first in the only tie featuring two previous World Cup qualifiers, must do without goalkeeper Itumeleng Khune.
The 28-year-old from Kaizer Chiefs, who is among the best shot-stoppers in Africa, suffered a training-ground knee injury and faces an operation.
Bafana Bafana coach Ephraim 'Shakes' Mashaba has set his team an ambitious target of winning in coastal city Benguela.
"We have to ensure we win away and then consolidate that success by scoring a few more goals in the return match," he said.
Cameroon, who hold the African record for World Cup appearances with seven, visit Niger, scorers of six unanswered goals in home and away first-round victories over Somalia.
The closest ties, judged by rankings, could be Benin against Burkina Faso and four-time qualifiers Morocco against Equatorial Guinea, with just 10 world places dividing them.