OBJECTIVES: Previous studies have demonstrated substantial variation of the relative efficacy of widely used drugs over time. Changes in population characteristics or variation in the placebo response may be potential influencers. We used tiotropium as a treatment to examine this phenomenon as it has commonly been used as a reference treatment over time in Chronic Obstructive Pulmonary Disease (COPD). We aimed to assess the evolution of the relative efficacy of inhaled tiotropium against placebo, between launch and the latest assessment. METHODS: We performed a systematic literature review of randomized-controlled trials (RCTs) of adults suffering from COPD in Medline from 2000 (launch) to 2012. RCTs evaluating tiotropium 18 µg as a maintenance treatment for COPD were included in the analyses. Efficacy outcomes evaluated included change from baseline in trough forced expiratory volume in 1 second (FEV) and COPD exacerbations leading to hospitalizations. Efficacy of tiotropium was presented as the mean difference to placebo. RESULTS: Difference in change from baseline in FEV versus placebo was evaluated in 21 RCTs. The relative effect of tiotropium increased over time, ranging from 0.084 to 0.150 in 2000 (launch) and from 0.120 to 0.189 in 2012. Difference in rates of exacerbations versus placebo was reported in 24 studies. The relative effect of tiotropium was found to decrease over time for this outcome. This trend was partly explained by an increase in placebo effect. CONCLUSIONS: We identified variations in the relative efficacy of tiotropium over time on two major outcomes for assessing drug relativeness effectiveness in COPD. Further research is required to understand these changes and the implications for evaluating the relative effectiveness of a new drug versus already marketed ones. Time of marketing authorization may not be the appropriate time to assess the relative effectiveness of a new drug.