Osteomyelitis is a significant complication of sickle cell disease (SCD), and several factors contribute to its pathogenesis, including altered expression of proinflammatory and anti-inflammatory cytokines. In view of the role of interleukin-10 (IL-10) as an anti-inflammatory cytokine, we tested the notion that SCD osteomyelitis is associated with a reduction in IL-10 secretion and, hence, precipitation of a proinflammatory state. Study subjects comprised 52 SCD patients with confirmed diagnosis of osteomyelitis and 165 age-and gender-matched SCD patients with negative histories of osteomyelitis. Results obtained showed that IL-10 serum levels in SCD osteomyelitis patients were significantly lower than those of control SCD patients. Receiver operating characteristic (ROC) analysis demonstrated that altered IL-10 serum levels predicted the development of osteomyelitis, and the mean area under ROC curves of IL-10 was 0.810 among SCD patients with osteomyelitis. A systematic shift in IL-10 serum levels toward lower values was seen in osteomyelitis cases, with an increased osteomyelitis risk associated with decreased IL-10 levels. Multivariate logistic regression analyses confirmed the independent association of reduced IL-10 with osteomyelitis after controlling for sickle hemoglobin (HbS), fetal hemoglobin (HbF), platelet count, and white blood cell (WBC) count. These data support the strong association of decreased IL-10 levels with osteomyelitis, thereby supporting a role for IL-10 in osteomyelitis follow-up.