Abstract Non-Human Leukocyte Antigen (HLA) genes have concomitant, although modest, effects on multiple sclerosis (MS) susceptibility; however findings have varied in different populations. Here we present the results of an association study of 16 single nucleotide polymorphisms (SNPs) in 10 non-HLA genes ( IL7R , IL2RA , CLEC-16A , TYK2 , CD58 , IRF5 , STAT3 , CTLA-4 , APOE , ICAM-1 ) in a Western Australian cohort of 350 MS patients and 498 population control subjects. Our results indicate that in this population, SNPs in IL7R , TYK2 , IRF5 and APOE have modifying effects on MS susceptibility. We also found evidence of interactive protective effects between polymorphisms in the IL7R / CD58 , CLEC-16A / CTLA-4 , and TYK2 / IRF5 genes, which in some instances are restricted within HLA- or gender-defined groups.