The clinical benefits of interferon (IFN) beta therapy in some multiple sclerosis (MS) patients are still unexplained, raising the question whether polymorphism within the IFNB gene itself would provide an explanation. Screening the IFNB gene by single strand conformation polymorphism (SSCP) analysis and sequencing, a single nucleotide polymorphism was identified. Both alleles were distributed with similar frequencies in MS patients and controls. Significant linkage disequilibrium (LD) between the IFN allele [153C] and allele [02] of the previously analyzed IFNA microsatellite (Epplen et al. Ann Neurol 1997; 41: 341-352) was observed in MS patients only, indicating a disease related haplotype. On the other hand an increased risk (RR = 12.41; Pc < 8 x 10(-5)) was observed for allele [07]. Hence the study was extended to neighbouring genes. Functionally relevant polymorphisms, i.e., premature stop codons in the IFNA10 [Cys20Stop] and IFNA17 [58Stop] genes and an aminoacid (aa) substitution [ile 184Arg] in the IFNA17 gene were analyzed. Patients carrying a non-functional IFNA17 allele bear an increased risk to develop MS (RR = 25.68; Pc < 0.06). In addition, LD analysis between IFNA10 [Cys20Stop], IFNA17 [58Stop] and the IFNA microsatellite alleles provides evidence for IFNA14, IFNA16 or IFNA5 as additional, most likely candidate genes. The present study excludes the IFNB gene as a candidate for MS predisposition but provides first evidence for predisposing IFNA genes.