Abstract Context: Levels of dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) are inversely associated with cardiovascular mortality in men but not women. Very little evidence is available on the impact of DHEA administration on lipoprotein profile in women. DHEAS levels are very low/undetectable in hypoadrenal women. Objective: The objective of the study was to determine the impact of DHEA replacement on lipoprotein profile in hypoadrenal women. Design and Setting: A double-blind, randomized, placebo-controlled, cross-over design study was conducted at the Mayo Clinic. Participants: Thirty-three hypoadrenal Caucasian women (mean ± sd; age 50.3 ± 15.2 yr, body mass index 26.6 ± 4.4 kg/m2) took part in the study. Intervention: Study participants were assigned to receive either a placebo or 50 mg/d of DHEA for 3 months each. Lipid levels and lipoprotein profile were analyzed using the Lipo Science Lipoprotein nuclear magnetic resonance system. Main Outcome Measures: Changes in various lipoprotein sizes and levels were measured. Results: The DHEA period had higher plasma DHEAS levels than during placebo (<0.3 ± 0.0 vs. 3.5 ± 1.3 nmol/liter, P < 0.001). DHEA replacement significantly reduced total cholesterol (20.0 vs. −22, P = 0.02) and high-density lipoprotein (HDL) levels (2.0 vs. −6.0, P = 0.006) and tends to reduce triglyceride and total low-density lipoprotein levels. Although, DHEA replacement had no effect on low-density lipoprotein particle size, it significantly reduced larger HDL particles and to modest extent small HDL particles. Conclusions: Our study findings showed that oral DHEA administration in hypoadrenal women results in an unfavorable lipoprotein profile. The results warrant long-term studies to determine the impact of DHEA replacement on cardiovascular risk.