Recent studies have found that baseline inflammatory status affected the response of the lipid profile to diet intervention. The goal of this study was to determine whether baseline inflammatory status, as reflected in C-reactive protein, interleukin 6, and tumor necrosis factor α, affected the lipid and insulin response to a weight loss intervention. A second goal was to determine whether inflammatory markers were related to traditional metabolic risk factors, such as lipids and insulin, in our sample of 190 overweight (body mass index, 27-30 kg/m2) premenopausal women. Body composition, fat distribution, serum lipids, insulin sensitivity (Si), and markers of inflammation were assessed at baseline and after weight loss to body mass index <25 kg/m2. All measurements were taken after a 4-week period of weight maintenance. Mixed-model, repeated-measures analysis was used to determine whether the interaction of baseline inflammatory status and time was significant in determining the changes in metabolic risk factors (Si and lipids) with weight loss. Weight loss was associated with significant reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and insulin, and increases in high-density lipoprotein cholesterol and Si. Triglycerides were higher (P = .054) and Si lower (P = .057) with increasing C-reactive protein tertile. The interaction of baseline inflammatory status and time was not significant for any outcome variable of interest. These results do not support the hypothesis that baseline inflammatory status affects the lipid and insulin response to a weight loss intervention. However, in these young, healthy women, weight loss had a beneficial impact on both inflammatory status and risk factors for chronic metabolic disease. © 2008 Elsevier Inc. All rights reserved.