Assessing polar bear (Ursus maritimus) immune function in relation to environmental stressors, including habitat change, nutritional stress, pathogen prevalence, and pollution, has been identified as critical for improved understanding of the species' health. The objectives of this study were two-fold: 1) to assess the role of climate-associated factors (habitat use, body condition) in explaining the plasma concentrations of contaminants in southern Beaufort Sea (SB) polar bears, and 2) to investigate how climate-associated factors, contaminant concentrations, and pathogen sero-prevalence influence the plasma concentrations of immune-signaling proteins called cytokines. A commercially available multiplex canine cytokine panel was validated for the quantification of five pro- and anti-inflammatory cytokines in polar bear plasma: tumor necrosis factor alpha (TNF-a), interleukin 6 (IL-6), IL-8, IL-10, and interferon gamma-induced protein 10 (IP-10). This panel was then used to measure cytokine concentrations in 49 SB polar bears sampled in the springs of 2013 and 2014. Mean ?PCBs (plasma), ?OCs (plasma), and THg (hair) were 13.01 ± 1.52 ng g-1 w.w. (range: 0.17-52.63), 19.46 ± 1.17 ng g-1 w.w. (range: 6.63-45.82), and 0.49 µg g-1 d.w. (range: 0.99-15.18), respectively. Top models explaining variation in concentrations of plasma PCBs, plasma OC pesticides, and hair THg in SB polar bears included body mass index and/or habitat use (onshore versus offshore), with higher contaminant concentrations in leaner and/or offshore bears. Plasma cytokine concentrations were influenced most strongly by plasma PCBs and age, with little to no influence found for plasma OCs or hair THg concentrations, habitat use, or pathogen sero-prevalence. The lack of association between cytokines and these latter variables is likely due to a temporal disconnect between measured endpoints. The change of polar bear habitat use, feeding ecology, and body condition with ongoing climate warming is affecting exposure to contaminants and pathogens, with potential adverse consequences on a well-balanced immune system.