Although inflammation is associated with risk of gestational diabetes mellitus (GDM), little is known if there is an association between inflammation and GDM in African-American women, a group at higher risk for GDM complications. In the present study, we aimed to determine if selected inflammatory cytokines (i.e. TNF-α, hs-CRP, IL-6, IL-10, IL-6/IL-10 ratio, IL-1β) measured in the 2nd trimester, were associated with GDM risk in 185 pregnant African-American women. GDM was defined as a physician-documented GDM diagnosis, a fasting glucose between 92 and 125mg/dl, or evidence of glucose intolerance (defined using the 3-h glucose tolerance test). A total of 18 women (9.7%) had GDM. After covariate adjustment, C-reactive protein, measured at a mean 21.2±3.7 weeks gestation, was statistically significantly associated with GDM development (P=0.025); for every one-unit increase in log-transformed C-reactive protein, the odds of GDM increased by 5.3. Results were similar using a principal component analysis approach. This study provides evidence that higher levels of 2nd trimester C-reactive protein is associated with increased risk of GDM in African-American women. Further research is needed to examine whether C-reactive protein may be a useful early-pregnancy screen for evaluating potential GDM risk in African-American women.