Populations with insufficient ultraviolet exposure and who consume diets low in vitamin D have low vitamin D status (plasma 25-hydroxyvitamin D (25(OH)D) concentrations) and a reported higher incidence of multiple sclerosis (MS). The active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), is an effective anti-inflammatory molecule. No research to date has assessed 1,25(OH)2D3 concentrations in individuals with MS. In this study, plasma concentrations of 25(OH)D, 1,25(OH)(2)D-3 and parathyroid hormone (PTH) were measured in 29 individuals with MS and 22 age- and sex-matched control volunteers. There were no significant differences in plasma PTH, 25(OH)D and 1,25(OH)2D3 concentrations between individuals with MS and control volunteers. Women with MS had significantly higher 25(OH)D and 1,25(OH)2D3 concentrations than men with MS (79.1 +/- 45.4 versus 50.2 +/- 15.3nmol/L, P=0.019 and 103.8 +/- 36.8 versus 70.4 +/- 28.7pmol/L, P=0.019, respectively). There was a significant positive correlation between 25(OH)D and 1,25(OH)(2)D-3 concentrations in all subjects (r=0.564, P=0.000), but secondary analysis revealed that the correlation was driven by women with MS (r=0.677, P=0.001). Significant sex differences in vitamin D metabolism were observed and were most marked in individuals with MS ' suggesting that vitamin D requirements may differ between the sexes, as well as by underlying disease state.