Vaso-occlusive crisis (VOC) is a significant complication of sickle cell disease (SCD), and altered production of pro-inflammatory and anti-inflammatory molecules contributed to its pathogenesis. In view of the association of chronic inflammation with VOC onset, and given the capacity of interleukin (IL)-10 as anti-inflammatory, and IL-6, and TNFα as pro-inflammatory cytokines, we tested the association of altered IL-10, IL-6, and TNFα secretion with VOC pathogenesis and its severity. Study subjects comprised 147 SCD patients with active VOC (VOC Group), and 63 pain-free SCD patients for at least 9 months before blood collection (Steady-state Group). Serum cytokine concentrations were determined by ELISA. IL-10 levels were significantly reduced, while IL-6 levels were increased in VOC compared to Steady-state groups; serum TNFα levels were comparable between both groups. There was enrichment of low IL-10, but high IL-6 and TNFα quartiles in VOC Group, which translated into increased VOC risk. In contrast, high IL-10, but low IL-6 and TNFα quartiles were seen in Steady-state Group. Correlation analysis demonstrated significant association between reduced IL-10 levels and the frequency, type, severity, and duration of VOC and requirement for hydroxyurea treatment, while IL-6 correlated with duration of VOC episodes. Our data support strong association of reduced IL-10 and increased IL-6 levels with VOC, and their modulation of VOC-related parameters.