The 2004/2007 European Union (EU) enlargement by 12 member states offers a unique opportunity to quantify the impact of EU efforts to expand and integrate the scientific competitiveness of the European Research Area (ERA). We apply two causal estimation schemes to cross-border collaboration data extracted from millions of academic publications from 1996 to 2012, which are disaggregated across 14 subject areas and 32 European countries. Our results illustrate the unintended consequences following the 2004/2007 enlargement, namely, its negative impact on cross-border collaboration in science. First, we use the synthetic control method to show that levels of European cross-border collaboration would have been higher without EU enlargement, despite the 2004/2007 EU entrants gaining access to EU resources incentivizing cross-border integration. Second, we implement a difference-in-difference panel regression, incorporating official intra-European high-skilled mobility statistics, to identify migration imbalance-principally from entrant to incumbent EU member states-as a major factor underlying the divergence in cross-border integration between Western and Eastern Europe. These results challenge central tenets underlying ERA integration policies that unifying labor markets will increase the international competitiveness of the ERA, thereby calling attention to the need for effective home-return incentives and policies.