Despite the common belief that orientation asymmetry—fundamental differences in the goals and expectations between partners—constitute a major barrier to successful collaboration, empirical evidence on how orientation asymmetry impacts university-industry collaboration is rare. We seek to understand the nature and impact of orientation asymmetry by conducting a mixed-method study of the research collaborations between a Big Pharma and its academic partners. Our interviews reveal critical asymmetries between partners, concerning not only different orientations, but also different perceptions of conflict. Building on these qualitative findings, we conduct a multi-wave, multi-source survey study to unpack the relationships between orientation asymmetry, conflict within collaboration teams, conflict perception asymmetry, and different types of collaboration success. We contribute to the literature on university-industry collaborations by providing a much-needed comparison of the perspectives from both sides of the collaboration and developing a nuanced understanding of the dynamics within collaboration project teams. We discuss the implications of our findings for researchers, managers, and policymakers.