Abstract Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and disorders involving chronic inflammation are often co-morbid with major depression. Since healthy immune regulation is accomplished through counter-balancing effects of pro- and anti-inflammatory cytokines, we hypothesized that depressed subjects (compared to controls) would express lower concentrations of the anti-inflammatory/immunoregulatory cytokine interleukin (IL)-10, and a higher IL-6/IL-10 ratio. We also examined the possibility that depressed subjects may exhibit a deficiency in the regulatory loop involving IL-6 induced secretion of IL-10. Therefore, we hypothesized that circulating IL-6 and IL-10 would be positively correlated in controls, while the correlation would be weaker in depressed subjects. Resting state serum cytokine concentrations were quantified in 12 unmedicated depressed subjects, and 11 age, gender, and ethnicity-matched controls. Depressed subjects showed significantly lower IL-10 ( p = 0.03, Cohen’s d = −0.96), non-significantly higher IL-6, and significantly higher IL-6/IL-10 ratios ( p = 0.05, Cohen’s d = 0.50). Across all participants, higher scores on the self-rated Inventory of Depressive Symptoms were associated with lower IL-10 ( r(21) = −0.57, p = 0.005) and non-significantly higher IL-6/IL-10 ratios ( r(21) = 0.38, p = 0.07), but not related to IL-6 concentrations. As hypothesized, IL-6 and IL-10 concentrations were strongly and positively correlated in controls ( r(9) = 0.81, p = 0.003), but were completely dissociated in depressed subjects ( r(10) = 0.01, p = 0.98). These results suggest that lower IL-10 levels, a higher IL-6/IL-10 ratio, and the apparent absence of a counter-balancing, immunoregulatory increase in IL-10 in response to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression. Therefore, reduced induction/availability of IL-10, that would normally inhibit pro-inflammatory cytokine actions and resolve inflammation, may contribute to the depressogenic as well as the inflammatory disease-promoting effects of chronic, low-level elevations in pro-inflammatory cytokines.