Sickle cell anemia (HbSS) is characterized by hypermetabolism, chronic inflammation, and increased oxidative stress, but the relationship between these factors is undefined. In this study, we examined indicators of inflammatory process and markers of oxidative damage and their impact on resting energy expenditure (REE) in stable HbSS adolescents (n = 35) and healthy controls carrying normal hemoglobin genotype (HbAA) (n = 39). C-reactive protein (CRP), white blood cell (WBC) count, and proinflammatory cytokines were measured as markers of inflammation and 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoPM) as a marker of oxidative stress. REE was measured by indirect calorimetry. WBC counts (11.90 ± 5.3 ×103/μL versus 5.6 ± 1.9 ×103/μL; p < 0.001), serum CRP (9.1 ± 11.0 μg/mL versus 0.4 ± 0.7 μg/mL; p < 0.001) and serum IL-8 (7.5 ± 4.4 pg/mL versus 5.5 ± 4.8 pg/mL; p = 0.011) were higher in HbSS than HbAA, suggesting an anti-inflammatory response in HbSS. Higher urinary F2-IsoPM in HbSS (1.2 ± 0.4 versus 0.7 ± 0.3 ng/mg creatinine; p < 0.001) indicates increased oxidative stress. Fat free mass (FFM), hemoglobin (Hgb), interleukin (IL)-8, and F2-IsoPM were independent predictors of REE in HbSS (overall r2 = 0.778; p < 0.001). Low-grade inflammation and increased oxidative stress are present in adolescents with HbSS in the absence of acute crisis, and their markers are correlated with elevated REE.