Preclinical findings suggest that aspirin might inhibit pancreatic carcinogenesis, but epidemiological data are scanty and controversial. The role of aspirin use in pancreatic cancer is further analyzed in a multicentric hospital-based case–control study conducted in Italy between 1991 and 2008. Cases were 308 patients with incident pancreatic cancer and controls were 477 patients admitted to the same hospitals as cases for acute conditions, not related to risk factors for pancreatic cancer. A total of 22 cases (7%) and 37 controls (8%) reported regular aspirin use, with a corresponding adjusted odds ratio (OR) of 0.87 [95% confidence interval (CI): 0.47–1.61]. A slight protection, although not significant, was observed for duration of use ≥5 years (OR=0.53; 95% CI: 0.21–1.33) and for time since first use ≥10 years (OR=0.69; 95% CI: 0.25–1.93). The risk of pancreatic cancer was significantly below unity for current users of ≥5 years (OR=0.23; 95% CI: 0.06–0.90), but the risk was based on three cases and 16 controls only. We observed no association between regular aspirin use and pancreatic cancer risk, although our results suggested a possible protective effect for long-term current users.