It has been hypothesized that the observed excess risk of multiple myeloma (MM) among obese persons could be the result of altered circulating levels of adipokines, polypeptide hormones with pro- and anti-inflammatory properties secreted by adipose tissue. We investigated whether circulating levels of leptin, total adiponectin, and high molecular weight adiponectin are associated with subsequent MM risk among 174 MM patients and 348 controls within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Inverse associations with MM were observed for total adiponectin (highest quartile vs lowest: odds ratio = 0.49; 95% CI = 0.26-0.93, P(trend) = .03) and high molecular weight adiponectin (0.44; 0.23-0.85, P(trend) = .01). These associations remained after restricting to MM patients diagnosed ∼ 8 years or more after blood collection. Leptin levels were not associated with MM risk. The results of this study, to our knowledge the first prospective investigation of circulating adipokines and MM, suggest that adiponectin may play an important role in obesity-related myelomagenesis.