Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Gender influences both susceptibility to MS, with the disease being more common in women, and the clinical course of disease, with an increased proportion of males developing the primary progressive form of the disease. The basis for these differences may include genetic and immunological factors, and the immunological differences between men and women may be influenced by the effects of the sex hormones. Over several years we have collected blood from MS patients and controls, and measured T-cell responses to myelin proteolipid protein (PLP) and myelin basic protein (MBP) and have shown increased responses to PLP in MS patients compared to healthy controls and patients with other neurological diseases. In the present study we analyzed data from over 500 individuals, to determine whether there are differences between males and females in their responses to PLP and MBP. We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals. We suggest that this may be relevant to the higher prevalence of MS in women.