Objective. To determine whether there are specific cytochrome P450 (CYP2) alleles that increase susceptibility to scleroderma in individuals who have been exposed to organic solvents. Methods. CYP alleles at 2 loci, 2E1 and 2C19, were compared in 7 patients who had developed scleroderma after exposure to solvents versus 71 patients with scleroderma without solvent exposure ("sporadic" disease) and 106 population controls. Results. The 2E1*3 allele was found in 2 of the 7 patients who had been exposed to organic solvents, with a greater frequency than occurred in either the disease controls or the population controls (odds ratio [95% confidence interval] 9.1 [1.5-59.1] and 10.2 [1.8-62.2], respectively). All 7 patients with solvent exposure carried the 2C19EM genotype, compared with 89% of patients with sporadic scleroderma. Conclusion. Our results suggest that alleles at CYP loci may be involved in increasing susceptibility to scleroderma among subjects who have been exposed to organic solvents.