In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II‐associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib‐pair families, 222 British sib‐pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA‐DR DQ haplotype, and the Norwegian case‐control samples were also typed for HLA‐A and ‐B loci. In the Norwegian sporadic MS patients association was seen with HLA‐A, HLA‐B, and with the D6S265 marker, located 100 kb centromeric to HLA‐A. Associations with HLA‐A and D6S265 loci were also suggested when restricting the analysis to HLA‐DR15 haplotypes. In the sib‐pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA‐DR15 and ‐A3 (GRR = 15), compared to those who carry only HLA‐DR15 (GRR = 7), only HLA‐A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA‐DR15 and ‐A3 (odds ratio (OR) = 5.2). These results suggest that HLA‐A or a gene in linkage disequilibrium with it may contribute to the HLA class II‐associated genetic susceptibility to MS.