© 2015 Informa UK, Ltd. Objective. Use of odds ratio (OR) in randomized controlled trials (RCTs) has been criticized because it overestimates the effect size, if incorrectly interpreted as risk ratio (RR). To what extent does this make a difference in the context of clinical research is unclear. We, therefore, aimed to address this issue considering its importance in evidence-based practice of medicine. Methods. We reviewed 580 RCTs published in the New England Journal of Medicine between January 2004 and June 2014 and identified 107 RCTs that reported unadjusted RR (n = 76) or OR (n = 31) for the primary outcome. For studies reporting ORs, we calculated RRs, and vice versa, using Stata software. The percentage of divergence between the reported and calculated effect size estimates was analyzed. Results. None of the RCTs showed a statistically significant result becoming insignificant or vice versa depending on the effect size estimate. OR exaggerated the RR in 62% of the RCTs. The percentage of overestimation was > 50% in 28 RCTs and > 100% in 13 RCTs. The degree of overestimation was positively correlated with the prevalence of outcomes (spearman’s rho = 0.84 and 0.66, p <0.001). Conclusion. Use of OR instead of RR in RCTs does not change the qualitative inference of results. However, the use of OR can markedly exaggerate the effect size in RCTs if misinterpreted as RR and, hence, has the potential to mislead clinicians.