The conclusion of most international agreements by the EU requires the consent of the European Parliament (EP). Yet, besides activating its veto power, the EP can also challenge the ratification of international agreements by delaying the consent procedure, by threatening to deny consent, or by a committee recommending to deny consent. Such ratification challenges affect the EP’s relation with the Commission, which acts as the EU’s negotiator and which can be confronted with a failure to deliver its international commitments. While the EP has indeed the powers to challenge the ratification of international agreements and while ratification challenges do sometimes happen, the EP also has an incentive to give its consent, for both reputational and policy reasons. Starting from this puzzle, the paper asks: under which conditions does the EP challenge the ratification of international agreements? Relying upon a crisp-set Qualitative Comparative Analysis (csQCA) of 22 agreements negotiated since 2010, we analyse four explanatory conditions of EP ratification challenges: (1) the existence of ad hoc practices of interaction between the EP and the Commission in the policy field of the agreement; (2) the actual mobilisation of such practices during the mandate-preparation and the negotiation phases; (3) the salience of the agreement in the public sphere; (4) the EP’s pursuit of policy-shaping rather than scrutiny goals. The paper makes two main contributions: applying a comparative approach on EP-Commission relations, (1) it sheds light on both highly and lowly politicized negotiations, and (2) it goes beyond mere veto activation by considering the broader ratification challenges.