To measure the proportion of cases of retinitis pigmentosa (RP) caused by mutations in the peripherin/RDS (RDS) and ROM1 genes. The single-strand conformation polymorphism (SSCP) method was used to analyze 227 unrelated patients with dominant or recessive RP for mutations in the RDS gene and an overlapping set of 315 unrelated patients for mutations in the ROM1 gene (excluding patients with other known RP genes). Variant bands revealed by SSCP were studied further by polymerase chain reaction-based, direct genomic sequencing and, where possible, by cosegregation analysis in the families of the index cases. Four index patients were found to have RP as a result of one of four dominant mutations in the RDS gene, two of which are novel. Four other index patients were found to have digenic RP as a result of the combination of heterozygous mutations in both the RDS and the ROM1 gene, with one of the ROM1 mutations being novel. The digenic cases all had the same RDS mutation (the missense change Leu185Pro), but each had one of three different ROM1 mutations. The authors were unable to determine through cosegregation analysis whether three other changes encountered in the RDS gene and five in the ROM1 gene were pathogenic. The authors found mutations in the RDS gene as a cause of dominant or digenic RP and mutations in the ROM1 gene as a cause of digenic RP. No cases of RP caused by ROM1 mutations alone have been discovered thus far. Mutations in the RDS and ROM1 genes are infrequent causes of RP, together accounting for only a few percent of patients in the United States and Canada.