Some polymorphisms in the FCRL3 gene, a member of the Fc-receptor like family, have been associated with several autoimmune diseases and recently with multiple sclerosis (MS). We performed a case-control study of three SNPs in FCRL3 gene in 645 MS patients and 786 controls, all Caucasians from the South of Spain. Genotype and allele frequencies of two SNPs (rs7528684/FCRL3_3 and rs7522061/N28D), which were in high linkage disequilibrium (r(2) = 0.87), differed between MS cases and controls. The C allele of FCRL3_3 was found to be protective for MS (per allele OR = 0.81, 95% C.I. = 0.70-0.94; P-value = 0.007) as was the G variant of N28D, but no association was found for rs11264799/FCRL3_4. Haplotype analysis confirmed these associations with highly consistent effect sizes for haplotypes carrying the C allele of FCRL3_3.