Background. Obesity is a disorder often accompanied by a heightened state of systemic inflammation and immunoactivation. The present randomized crossover trial aimed to investigate the efficacy of curcumin, a bioactive polyphenol with established anti-inflammatory and immunomodulatory effects, on the serum levels of a panel of cytokines and mediators in obese individuals. Methods. Thirty obese individuals were randomized to receive curcumin at a daily dose of 1 g or a matched placebo for 4 weeks. Following a 2-week wash-out period, each group was assigned to the alternate treatment regimen for another 4 weeks. Serum samples were collected at the start and end of each study period. Serum levels of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFNγ, EGF, MCP-1, and TNFα were measured using a multiplex Biochip Array Technology based method. Results. Mean serum IL-1β (P = 0.042), IL-4 (P = 0.008), and VEGF (P = 0.01) were found to be significantly reduced by curcumin therapy. In contrast, no significant difference was observed in the concentrations of IL-2, IL-6, IL-8, IL-10, IFNγ, EGF, and MCP-1. Conclusions. The findings of the present trial suggested that curcumin may exert immunomodulatory effects via altering the circulating concentrations of IL-1β, IL-4, and VEGF.