The potential relevance of chromosome 7q21-22 in susceptibility to multiple sclerosis (MS) has been highlighted in genome-wide linkage screens as well as in association studies of 7q-specific polymorphic microsatellites. Especially, recent, independently performed studies have provided evidence for significant association of the markers D7S554 and D7S3126 with MS in Sardinian, Northern Irish and Spanish-American cohorts. The gene most closely located to these markers is the neuropeptide preprotachykinin-1 (TAC1) gene. Both its position and the array of biological functions exerted by its expression products make it a logical primary choice for further scrutiny as the putative chromosome 7q21-22 MS susceptibility gene. We report identification of eight polymorphisms in this gene by means of a sequencing approach. A Northern Irish case-control was typed for six of these polymorphisms. One of these, an intron 1 single-nucleotide polymorphism (SNP), showed significant association with MS (P=0.009). Two-marker haplotypes composed of allelic combinations of TAC1 promoter-intron 1 SNPs were highly significantly associated with MS and more so with the relapsing-remitting form of this disease. While independent reproduction of these data in other data sets is indicated, our work is suggestive for a role of the TAC1 gene in MS. Genes and Immunity (2005) 6, 265-270. doi:10.1038/sj.gene.6364175 Published online 24 February 2005.