Background: It is unclear whether obstructive sleep apnea (OSA) is independently associated with increased levels of the acute-phase reactant C-reactive protein (CRP). The purpose of this study was to evaluate the relationship between OSA and high-sensitivity CRP (hs-CRP) levels according to the presence or absence of metabolic syndrome (MetS). Methods: This study recruited 245 male bus drivers from one transportation company in Taiwan. Each participant was evaluated by a polysomnography (PSG) test, blood lipids examination, and hs-CRP. Severity of OSA was categorized according to the apnea-hypopnea index (AHI). Results: Subjects were categorized into severe OSA group (n = 44; 17.9 %), moderate and mild OSA group (n = 117; 47.8 %), and non-OSA group (n = 84; 34.3 %). AHI had a significant association with hs-CRP (β = 0.125, p = 0.009) adjusting for age, smoking, drinking, and MetS status. Hs-CRP was elevated with severe OSA (β = 0.533, p = 0.005) even adjusting for BMI and MetS. Moreover, there was an independent effect for adjusted odds ratios (AORs) between the stratification of the severity for OSA and MetS. Conclusion: Elevated hs-CRP level is associated with severe OSA, independent of known confounders. The effect of OSA in CRP is independent of MetS was identified.