Background  The safety of NSAIDs is often evaluated by comparison with placebo in clinical trials.

Aim  To investigate the incidence of gastric and duodenal ulcers (GDU) in placebo arms in NSAID trials over the last three decades.

Methods  Randomized placebo-controlled trials of oral NSAIDs from 1975 to 2006 were systematically reviewed. The pooled incidence of GDU in placebo arms was calculated and compared. Meta-regression was used to identify risk factors related to the incidence of the placebo ulcer at the study level.

Results  Thirty-six studies met inclusion criteria (duration of 6.5 days to 24 weeks). In total, 3.29% GDUs were reported in 36 placebo arms. The incidence of GDU in placebo arms was 0, 4.20% and 3.03% in the studies from 1975–1989, 1990–1999 and 2000–2006 respectively (P > 0.05). Eligible subjects with previous GI events and eligible subjects on co-therapy with low-lose aspirin/corticosteroids were associated with the increase in placebo ulcer incidence after adjusting for other factors.

Conclusions  The incidence of GDU in placebo arms has not changed significantly over the last three decades, although has decreased in the past 10 years. Studies show that previous GI events and co-therapy with low-dose aspirin/corticosteroids were associated with increasing GDU in placebo arms.