Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with upper gastrointestinal complications such as bleeding or perforation. Paracetamol has been traditionally considered a safer alternative to NSAIDs. In a previous case-control study we found that paracetamol at high doses increased the risk of upper gastrointestinal complications. We proposed to review all studies addressing the association between paracetamol and upper gastrointestinal complications and placed our results in the context of existing literature. We conducted a nested case-control study using the United Kingdom General Practice Research Database during the period between April 1993 and October 1998. Then we performed a systematic review of the literature indexed in MEDLINE published between 1980 and 2004. We identified a total of twelve studies that assessed the association between paracetamol and upper gastrointestinal complications. We used a fixed effects model to calculate a summary estimate of these studies. In the nested case control study, use of paracetamol was associated with a small elevated risk of upper gastrointestinal complications (relative risk (RR), 1.3; 95% confidence interval (CI), 1.1-1.5). The RR was 3.6 (95% CI, 2.6-5.1) among paracetamol users of more than 2 g daily, whereas smaller doses did not increase the risk. Among the twelve studies identified in the systematic review, estimates ranged from 0.2 through 2.0 with a summary estimate of 1.3 (95% CI, 1.2-1.5). Our findings indicate that use of paracetamol at the doses most commonly used confer little or no increased risk of upper gastrointestinal complications. More data are needed to confirm or refute the suggestion that high-dose paracetamol is associated with an increased risk of upper gastrointestinal complications of the same magnitude as the one observed with traditional NSAIDs.