Many autoimmune diseases preferentially affect women; however, the underlying mechanisms for the sex differences are poorly understood. We examined sex-dependent differences in the immunologic response to myelin proteins in 22 multiple sclerosis (MS) patients and 22 healthy controls. Using ELISA spot assay (ELISPOT) methodology, interferon (IFN) gamma and IL-5 secretions were examined at the single cell level in response to overlapping proteolipid protein (PLP) peptides. As previously reported, we observed an overall disease effect in the IFNgamma response, such that MS patients were significantly higher than controls. With respect to PLP-induced IFNgamma secretion, both MS and control females responded higher than their corresponding males. Female MS patients demonstrated the highest responses compared to MS males or healthy controls of either sex. Although MS females had high IFNgamma responses to PLP, they had no IL-5 responses at all, suggesting strong Th1 skewing. In contrast, MS males had more IL-5 than control males, who lacked IL-5 responses. These IL-5 responses suggested that disease and gender are not independent, but rather interact to influence the cytokine response to myelin. The data suggest a gender bias towards Th1 responses in MS, which may contribute to the female predominance in this disease.