The EU is "too important to be discarded", Leanne Wood has said ahead of a head-to-head debate between Nigel Farage and Carwyn Jones on the issue.
Writing in the Sunday Times, the Plaid Cymru leader urged Wales to "speak with one voice".
The UKIP leader and Welsh first minister will lock horns on Monday at an event in Cardiff.
The UK is set to have a referendum by the end of 2017 on whether or not to remain a member of the European Union.
Ms Wood said the bid for EU reform was "legitimate" but added any concerns were "far outweighed" by the benefits EU membership brings to Wales' agricultural sector, higher education institutions and transport infrastructure.
She criticised Prime Minister David Cameron for allowing ministers to campaign for either side in the referendum, calling his decision "irresponsible and bizarre".
And she said the issue would "alter the terms of the debate" in the lead up to National Assembly elections in Wales on 5 May.