Previous studies of chromosome stability in the nevoid basal cell carcinoma syndrome have yielded inconsistent results and suffered from small sample sizes and less than optimal controls. We investigated chromosome fragility and sister chromatid exchange in 20 affected individuals from five multiplex pedigrees, and 15 first- or second-degree unaffected relatives. The percentage of case and control cells showing breaks or rearrangements was compared using a test of proportions. A similar procedure was used to compare site-specific sister chromatid exchanges in baseline cultures from affected persons and controls. No significant differences were noted for either chromosome fragility or sister chromatid exchange between the two groups. These results suggest that cancer susceptibility in the nevoid basal cell carcinoma syndrome is not caused by or manifested as chromosome instability.