DHEA (dehydroepiandrosterone) is a weak androgen with proposed efficacy in the treatment of mild to moderate lupus, and possible beneficial effects on cardiovascular risk and bone mineral density. We hypothesized that treatment with 200 mg a day of Prasterone (DHEA) would improve pre-clinical measures of atherosclerosis: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), and circulating apoptotic endothelial cells (CD 146(AnnV +)), as well markers of bone metabolism. Thirteen premenopausal female patients with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) <or=8 were enrolled in a double-blind placebo-controlled crossover trial for 22 weeks with a 6-week washout between treatment periods. Results reveal high-density lipoprotein (HDL) levels significantly decreased with Prasterone (48.5 versus 56.3 with placebo, p <or= 0.001), and there was a trend towards impairment of endothelial function with Prasterone (brachial artery FMD 3.4% versus 4.4% with placebo, mean difference -1.07, NMD 19.5% versus 24.4% with placebo, mean difference -4.9, p = NS). There were no differences between groups in SLEDAI, CD146( AnnV+) cells, or receptor activator for nuclear factor kB ligand (RANKL)/osteoprotegerin, although RANKL was higher after treatment with Prasterone (mean difference -29.5 units; p = 0.097). This pilot study does not support the use of Prasterone in mild lupus for prevention of atherosclerosis or osteoporosis, and confirms other findings of potentially harmful effects on lipids.