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Abstract: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. The cytotoxic T lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analysed the CTLA4 +49A/G and CT60 polymorphisms in a cohort of 120 MS trio families recruited from the Flanders region in Belgium. Both polymorphisms were genotyped by polymerase chain reaction—restriction fragment length polymorphism (RFLP). The +49 G-allele was significantly more transmitted to affected probands (P =0.005). No transmission distortion was observed for the CT60 polymorphism. Haplotype analysis revealed significant overtransmission of the +49 A/G*G–CT60*G haplotype (P =0.0025), and undertransmission of the +49 A/G*A–CT60*G haplotype (P =0.015). The CTLA4 gene has been the focus of intense investigation in MS. Of 15 recently published papers, only six reported significant associations of various CTLA4 polymorphisms with MS, with the remainder being negative. Ours is the first report investigating the CT60 polymorphism in MS. Our data highlight a need for further scrutiny of the CTLA4 gene in MS. [Copyright &y& Elsevier]