Activation of innate inflammatory pathways, marked by increased production of pro-inflammatory cytokines, has been proposed as a potential mechanism linking poor sleep and inflammatory disease risk. In the present study, we examined associations of self-reported sleep quality and duration, and a calculated measure of sleep debt with the production of pro-inflammatory cytokines, interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha among a community sample of 156 healthy adults. Bivariate correlations revealed an inverse association between sleep quality and production of all the three pro-inflammatory cytokines that was retained for IL-1beta after controlling for demographic and health characteristics. Hierarchical linear regressions also revealed that higher sleep debt scores predicted greater production of IL-1beta and IL-6 after adjusting for covariates. Secondary analyses showed an interaction between sleep debt and body mass index (BMI) in the prediction IL-1beta, suggesting that the impact of sleep debt on cytokine production is greater among participants with lower BMI scores. Further exploration of this potential psychophysiological pathway linking sleep difficulty and inflammatory disease susceptibility is warranted.