Objective: There is a bidirectional relationship between obesity and mood disorders, with each increasing the risk of developing the other. This relationship suggests that they have overlapping pathophysiologic mechanisms. Adipose tissue-derived hormones, or adipokines, regulate appetite and metabolism and have activity in limbic brain regions, making them potential shared etiologic factors between elevated body mass index (BMI) and mood disorders. However, the precise relationships between BMI, mood, and adipokines are unknown. Methods: We measured the serum levels of adiponectin, lipocalin-2, resistin, adipsin, and leptin in 53 people with early-stage DSMIV- defined bipolar disorder, diagnosed with the Mini-International Neuropsychiatric Interview, and 22 healthy comparison subjects. Participants were followed at the University of British Columbia Mood Disorders Centre between June 2004 and June 2012. We were primarily interested in determining, in patients, (1) whether BMI and recent mood episodes predicted adipokine levels and (2) whether adipokine levels in turn predicted subsequent mood relapses and change in BMI. Results: Using linear regression, we found that (1) past-6-month mood episodes predicted lower adiponectin (β = -0.385, P = .04) and adipsin (β = -0.376, P = .03) levels and higher lipocalin-2 levels (β = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (β = 0.482, P < .01). Furthermore, lower adiponectin (β = -0.353, P = .01) and leptin (β = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (β = 0.496, P < .01) and leptin (β = 0.421, P < .01) levels predicted BMI gain. Conclusions: Our results suggest that mood episodes and medication treatment contribute to adipokine abnormalities in bipolar disorder and that adipokines influence psychiatric illness course and BMI change. Adipokines may represent a novel pathophysiologic mechanism linking elevated BMI and mood disorders and deserve further study as potential mood-regulating molecules.