A prospective study of 1431 patients admitted to a general surgery department were followed up for a median of 6.2 years after discharge (7679 person-years of follow-up). We collected information on underlying conditions, including severity of illness, and healthcare-related variables. Relative rates of death and their 95% confidence interval (CI) were estimated using person-years as the denominator. Multiple-risk factors adjusted for relative rates (RR) were obtained using Poisson regression analysis. There were 172 deaths during the follow-up period after hospital discharge (2/100 person-years). Follow-up was complete in 91% of the cohort. There were no important differences in demographic characteristics or risk factors between patients followed up and those lost to follow-up. The death rate in patients with any hospital-acquired infection was 5.3/100 person-years, and the relative rate was 3.07 (95% CI: 2.20-4.24). After adjusting for the main predictors of mortality, we found an effect modification by the presence of chronic disease (P = 0.01 for the product-term between hospital infection and the diagnosis of chronic diseases). Among patients without any underlying chronic disease, hospital-acquired infection was related to a significantly higher long-term mortality (RR = 2.47, 95% CI: 1.24-4.91). In these patients, surgical wound infection yielded a RR of mortality of 3.44 (95% CI: 1.63-7.27). Among patients with underlying chronic disease no association between hospital infection and long-term mortality was found. No evidence of an important modification of the relative rate along the follow-up period was observed. In conclusion surgical patients without chronic disease developing hospital-acquired infection have an increased risk of long-term mortality.