BACKGROUND Reports of long-term incidence trends of endemic diarrhea-associated hemolytic uremic syndrome (D+HUS) are few and inconclusive. OBJECTIVE To define and analyze the incidence and outcomes of D+HUS over a period of approximately 25 years in a highly endemic region of southern Alberta. METHODS Annual incidence rates of confirmed cases of D+HUS were compared between two 12-year periods (1980 to 1992 and 1994 to 2006). Differences in therapies used, and some short- and long-term complications observed were also compared between the two periods. RESULTS The absolute yearly number of D+HUS cases was highly variable. The comparison between the 1980 to 1992, and 1994 to 2006 periods demonstrated a modest 8.8% decrease in the total number of cases. The population-based average annual incidence rates were not significantly different between the two time periods (3.33 cases versus 2.58 cases per 100,000 population per year, respectively; P=0.30). Only supportive care measures were used in the latter period. A mortality rate of lower than 1% in the latter period was one of the lowest ever reported for a large cohort of D+HUS patients. CONCLUSIONS The present long-term retrospective study of D+HUS in a highly endemic area documented a modest decrease in the absolute number of cases but no difference in the average annual incidence over an extended period of time.