Genome screens suggest that several genes, each contributing to a small extent, are involved in multiple sclerosis (MS) susceptibility. Simultaneous analysis of related genes may improve the power to detect such small effects. Interferon-gamma (IFN-gamma), mediating its effects through the IFN-gamma receptor, is a pleiotropic, pro-inflammatory cytokine for which a detrimental effect on the course of MS has been reported. The role of IFN-gamma receptor 1 (IFNGR1) and IFN-gamma receptor 2 (IFNGR2) gene polymorphisms has not been studied in MS, and, for the IFNG gene polymorphism there is only one previous study, which incorporates clinical, but not imaging, data. The aim of this study was to investigate whether polymorphisms in the IFNG and IFNGR1 and IFNGR2 genes are associated with susceptibility to MS, or disease characteristics, as defined by clinical and imaging criteria. Genotypes for IFNG, IFNGR1 and IFNGR2 were determined in 509 patients with MS and in 193 healthy controls. Patient files were reviewed for disease course, age at onset of disease, and rate of progression. Serial magnetic resonance imaging (MRI) data were available for 107 patients. No significant differences in the distribution of IFNG, IFNGR1 and IFNGR2 genotype and allele frequencies were found between patients and controls. A progressive, as opposed to a relapsing, onset was significantly more frequent in carriers of the IFNGR2 allele Arg64 (P = 0.028). Moreover, IFNGR2 allele Arg64 carriers had a lower black hole ratio than non-carriers (P = 0.016). No other associations with clinical parameters, such as age at onset or rate of progression, or with imaging parameters, were observed. The IFNG intron 1 gene polymorphism studied is unlikely to play a major role in MS susceptibility or disease course. The IFNGR1 and IFNGR2 gene polymorphisms studied do not exert an important influence on MS susceptibility, but allele IFNGR2*Arg64 may be associated with a progressive disease onset.