Background: Sickle cell disease (SCD) is a common hemoglobinopathy associated with high morbidity and mortality. While interleukin-6 (IL-6) contributes to elevated acute-phase protein levels in steady-state SCD, its relationship with disease severity remains unclear. This study investigated IL-6 as an inflammatory biomarker and its association with the clinical severity of SCD. Materials and Methods: This observational, cross-sectional study was conducted at the Department of Medicine, Srirama Chandra Bhanja Medical College and Hospital, Cuttack, from August 2023 to August 2024. Patients with homozygous sickle cell disease (HbSS), confirmed by hemoglobin (Hb) electrophoresis and in steady state, were included.Disease severity was classified according to van den Tweel et al.,and serum IL-6 levelswere measured using the Elecsys® IL-6 immunoassay kit. Result: Ninety-four patients were included in the study. Based on disease severity, patients were categorized into mild (n=53), moderate (n=18), and severe (n=23) groups. The mean age of the patients in the mild, moderate, and severe groups was 29.68 years, 27.83 years, and 31.57 years, respectively. There were no significant differences in mean Hb (P=0.43), total leukocyte count (P=0.19), hematocrit (P=0.80), mean corpuscular volume (P=0.31), or mean corpuscular hemoglobin (P=0.39) across groups. However, the mean (SD) serum IL-6 level was significantly higher in the severe group [109.86 (90.53) pg/ml] compared to the moderate [81.52 (60.94) pg/ml] and mild [48.75 (33.61) pg/ml] groups (P<0.001). Conclusion: Serum IL-6 levels could serve as a useful marker for assessing the clinical severity of SCD, with higher IL-6 levels correlating with greater disease severity.