Background: Obesity is associated with an increased prevalence and severity of infections. The mechanism(s) responsible for the increased risk of infections is unclear. We evaluated the effects of excessive adiposity and weight loss on peripheral blood mononuclear cell (PBMC) chemokine (macrophage chemoattractant protein-1 [MCP-1) and cytokine (interferon-γ [IFN-γ]) production, which is an important component of the immune response to infectious pathogens. Methods: Lipopolysaccharide (LPS)- and phorbol 12-myristate 13-acetate plus ionomycin (PMA+I)-stimulated PBMC MCP-1 and IFN-γ production were determined in six extremely obese subjects (body mass index [BMI] = 62.4 ± 8.6 kg/m2) before and 1 year after gastric bypass surgery and in six age-matched lean subjects (BMI = 22.7 ± 1.4 kg/m2). Results: At baseline, LPS-stimulated MCP-1 production and PMA+I-stimulated IFN-γ production by PBMCs were 93.6% ± 4.9% and 88.8% ± 9.6% lower, respectively, in obese than in lean subjects (p < 0.03). Obese subjects lost 30.3% ± 10.6% of their body weight at 1 year after gastric bypass surgery (p < 0.001). Weight loss completely restored LPS-stimulated MCP-1 production and PMA+I-stimulated IFN-γ production in obese subjects to normal. Conclusions: Agonist-stimulated production of IFN-γ and MCP-1 are markedly suppressed in subjects with extreme obesity. Weight loss completely normalizes the ability of stimulated PBMCs to produce MCP-1 and IFN-γ. These findings could have important implications in understanding the increased risk of infections associated with obesity, and demonstrate a unique beneficial effect of weight loss on immune function.