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Recent reports have suggested increases in Buruli ulcer (BU), an infection caused by Mycobacterium ulcerans in west Africa. In 1991, we conducted surveillance for BU in a rural area of Cote d'Ivoire and identified 312 cases of active or healed ulceration. A case-control study was then performed to investigate risk factors for this infection. The rate of illness did not appear to differ between males and females (5.2% versus 7.5%; P = 0.11). The highest rate of illness was seen in the 10–14-year-old age group (143 cases per 1,000 population). New cases increased more than three-fold between 1987 and 1991, and local prevalence of BU was as high as 16.3%. Twenty-six percent of persons with healed ulcers had chronic functional disability. Participation in farming activities near the main river in the region was identified in the case-control study as a risk factor for infection (odds ratio [OR] for each 10-min decrease in walking distance between the fields and the river = 1.52, 95% confidence interval [CI] 1.01, 2.28, P = 0.046). Wearing long pants was protective (OR 0.20, 95% CI 0.06, 0.62, P < 0.005). We conclude that the incidence of BU is increasing rapidly in Cote d'Ivoire. Specific causes of this increase were not identified, but wearing protective clothing appeared to decrease the risk of disease.