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. Weobserved 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 _h17 lymphocytes in MS.