Four CTLA4 polymorphisms were investigated in a Northern Irish collection of relapsing–remitting (RR) and primary-progressive (PP) multiple sclerosis (MS) patients. The CTLA4 promoter (−318 C/T), exon 1 (+49 A/G) and intergenic CT60 SNPs, as well as a microsatellite found in the 3′ UTR (AT n ) were analysed in 246 RRMS, 84 PPMS and 158 healthy controls. The A allele of the exon 1 +49 A/G SNP (OR=1.36; 95% CI=1.11–1.81; P=0.038), and more so the AA genotype (OR=1.70; 95% CI=1.11–2.60; P=0.015) were associated with RR, but not PPMS. In the PPMS population, overall allele distribution of the AT n microsatellite was significantly different from that in the healthy controls. We did not find any association with the promoter (−318 C/T) or intergenic CT60 SNPs in either of the disease cohorts. In concordance with several recent studies, we detected a trend toward higher carriage rates of the +49 G allele in PP vs RR MS patients (66.7% vs 58.9%), though this was not significant. Our data highlight the CTLA4 +49 A/G and 3′UTR polymorphisms as potential modifiers of disease course in MS.