Recent genome-wide association studies have implicated the "signal transducer and activator of transcription 3" gene (STAT3) as a putative new multiple sclerosis (MS) susceptibility locus. However, independent validation studies are sparse. Therefore, we performed a genetic association study of two STAT3 polymorphisms (rs744166 and rs2293152) in a large and independent German case-control sample of 5,904 subjects. We observed a nominally significant, albeit weak association between rs744166 and MS susceptibility (odds ratio = 1.09, P = 0.012) in our sample. This study supports the association between STAT3 and an increase in MS risk. Taking into account the functional role of STAT3, our results favour an involvement of T(h)17 lymphocytes in MS.