Context: In recent years there has been increasing interest on publication bias and on initiatives to decrease bias, in- cluding trial registration. Objective: To test whether there has been an increase in reports of randomized control trials (RCT’s) with negative outcomes in major journals and to identify factors associated with these reports. Design: Retrospective review of reports of RCT’s published in the Journal of the American Medical Association, The Lancet and the New England Journal of Medicine before (2002-’03, pre-registration era) and after (2007-’08, registration era) the institution of mandatory trial registration. Main Outcome Measure: The primary outcome was the proportion of RCT reports with negative outcomes compared across the two eras. Secondary outcome includes other factors affecting pub-lication. Results: We identified 917 reports of RCT’s published in the two study eras. No publications in the pre-registration era reported trial registration compared with 94.4% in the registration era (p < 0.001). There was a non-significant increase in negative trials from the pre-registration to the registration era (29.1% vs. 34.1%, p = 0.10, OR 1.26, 95% CI 0.96 - 1.67). Study characteristics associated with negative outcomes include trials of drugs (OR 1.62, 95% CI 1.08 - 2.43), procedures or devices (OR 2.08, 95% CI 1.29 - 3.35), explicit identification of a single primary endpoint (OR 1.70, 95% CI 1.40 - 2.47), and increasing sample size (OR 3.08, 95% CI 1.78 - 5.34). Non-inferiority study design was associated with a decreased likelihood of a negative outcome (OR 0.13, 95% CI 0.05 - 0.31). Conclusions: The proportion of published RCT reports with negative outcomes in three major medical journals has not significantly increased since the mandatory clinical trial registration policy. The observed prevalence of negative trials is associated with increases in sample size and greater specificity in trial endpoints.