The authors investigated a reported incidence cluster of multiple sclerosis (MS) cases in a small, north-central Illinois community to determine validity and statistical significance. DePue, Illinois--a small, north-central Illinois community--has previously been the site of significant environmental heavy-metal exposure from a zinc smelter. Significant contamination of soil and water with zinc and other metals has been documented in this community during the time period of interest. In the mid-1990s, several cases of MS were reported to the Illinois Department of Public Health within the geographic limits of this community. Available medical records from purported MS cases reported to the Illinois Department of Public Health were reviewed, and living individuals were seen and examined. Statistical analyses were conducted with clinically definite MS cases; onset dates were determined by first symptom, and expected incidence rates were determined from published epidemiologic studies. Nine new cases of clinically definite MS occurred among residents of DePue, Illinois, during the period between 1971 and 1990. Seven of the 8 living subjects included in the final analyses were examined by one author (RS). The computed incidence rate deriving from these cases within DePue Township, Illinois, represented a statistically significant excess of new MS cases over expected. During the period from 1971 through 1990, a significant excess of MS cases occurred within the population of DePue, Illinois. Significant exposure of this population to mitogenic trace metals, including zinc, was also documented during this time period.