Background: Contradictory findings from randomized trials addressing similar research questions are not uncommon in medicine. Although differing results may reflect true differences in the treatment effects or in the deliverability of the intervention, more commonly it is as a consequence of small but important discrepancies in study design. Methods: The writing group selected 4 recent trials with apparently contradictory results (2 on revascularization for left main coronary stenosis and 2 on treatment of secondary mitral regurgitation). Detailed methodologic analysis was performed to elucidate the difference in findings. Results: Differences in the definition of the primary outcome are the most likely explanation for the contradictory findings of NOBLE versus EXCEL. Differences in study design (leading to substantially different patient populations) and in outcome definition might explain the discrepant findings of MITRA-FR versus COAPT. Conclusions: As shown by the comparative analysis of NOBLE and EXCEL and MITRA-FR and COAPT, changes in study design, outcome definitions, and patient population can markedly affect the outcome of randomized clinical trials.