The objectives of this study were to assess the relationship between inflammation and obstructive sleep apnea (OSA) and determine whether the lifestyle program's effects on inflammatory markers are associated with changes in anthropometric parameters, cardiorespiratory fitness, sleep duration, and OSA severity in severely obese adolescents. Participants were aged 14.6 (SD 1.2) yr, with a body mass index (BMI) of 40.2 (SD 6.5) kg/m2. Sleep, anthropometric parameters, glucose metabolism, inflammatory profile, and cardiorespiratory fitness [V̇o2peak relative to body weight (V̇o2peakBW) and fat-free mass (V̇o2peakFFM)] were assessed at admission and at the end of a 9-mo lifestyle intervention program (LIP). Associations between C-reactive protein (CRP) concentrations and BMI, sex, oxygen desaturation index (ODI), sleep fragmentation, total sleep time (TST), and V̇o2peak were assessed via ANCOVA. Twenty-three subjects completed the study. OSA subjects ( n = 13) exhibited higher CRP concentrations and a trend for higher BMI than non-OSA subjects ( P = 0.09) at admission. After intervention, OSA was normalized in six subjects, and CRP significantly decreased in the OSA group and in the whole population. In both groups, leptin levels significantly decreased, whereas adiponectin concentrations increased. At admission, BMI adjusted for sex, arousal index, ODI, TST, and V̇o2peakBW was associated with CRP levels (adjusted r2 = 0.32, P < 0.05). The decrease in CRP concentrations postintervention was associated with enhanced V̇o2peakFFM adjusted for sex, weight loss, and changed sleep parameters (adjusted r2 = 0.75, P < 0.05). Despite higher amounts of CRP in OSA subjects, obesity severity outweighs the proinflammatory effects of OSA, short sleep duration, and low cardiorespiratory fitness. However, enhanced cardiorespiratory fitness is associated with the decrease of inflammation after controlling for the same parameters.