Background: The maternal immune system undergoes substantial changes to support healthy pregnancy. Although obesity is a primary driver of inflammation and predictive of perinatal complications, additive effects of pregnancy and obesity on changes in inflammatory processes are not well delineated. Methods: This study examined serum proinflammatory markers interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, IL-1β, and C-reactive protein (CRP) during each trimester of pregnancy and 4–6weeks postpartum among 57 women. Results: Overall, IL-6 showed an increasing trend across pregnancy and significant increase at postpartum. Similarly, TNF-α increased significantly across gestation, with a further increase at postpartum. Both IL-8 and IL-1β showed a U-shaped curve, decreasing from early to later pregnancy, and increasing at postpartum. Finally, serum CRP decreased significantly across pregnancy, with further decreases at postpartum. Maternal obesity predicted higher IL-6 at each study visit. Obese women showed a trend toward elevated serum CRP during pregnancy, and significantly higher levels at postpartum. Discussion: The course of pregnancy and postpartum is characterized by significant changes in serum proinflammatory mediators. Obese women show elevations in serum proinflammatory markers relative to normal weight women during pregnancy and postpartum. Further research is needed to determine the extent to which obesity-induced inflammation affects maternal and fetal health.