Individuals with obstructive sleep apnea (OSA) have elevated levels of inflammatory markers, but no prospective study has examined the role of inflammation in the development of OSA.Is C-reactive protein (CRP) prospectively associated with risk of developing OSA?We followed 1,882 women from the Nurses' Health Study (NHS; 2002-2012), 3,854 women from NHSII (1995-2013), 3,075 men from the Health Professionals Follow-up Study (HPFS; 1996-2012) and 1,919 women and men from the Multi-Ethnic Study of Atherosclerosis (MESA; 2000-2012) who did not have diagnosed OSA at baseline and for whom CRP levels were available. In NHS/NHSII/HPFS, clinician-diagnosed OSA was self-reported. In MESA, at-home polysomnography was performed and OSA was identified as an Apnea-Hypopnea Index≥30. Logistic regression was used to estimate the odds ratio (OR) for OSA risk according to baseline CRP level, adjusted for multiple inflammation-related factors.After multivariable adjustment not including BMI, the pooled OR (95% CI) for OSA risk per doubling of baseline CRP level was 1.24 (1.18, 1.30). Additional adjustment for BMI substantially attenuated the association (pooled OR: 1.07; 95% CI: 1.01, 1.12). The fully-adjusted association was consistently stronger in individuals <55 years versus ≥55 years (p-interaction=0.01), in individuals with BMI<25 kg/m2 versus ≥25 kg/m2 (p-interaction=0.02) and in premenopausal versus postmenopausal women (p-interaction=0.002). CRP was more strongly associated with risk of OSA associated with excessive daytime sleepiness, high airway collapsibility and low arousal threshold (p-heterogeneity<0.05).Higher CRP was prospectively associated with increased OSA risk, particularly among younger individuals, underweight/normal-weight individuals or premenopausal women. The differential associations by OSA phenotype/endotype suggest possible mechanisms through which inflammation operates to modulate OSA risk. Given our reliance on a single CRP level measured a decade before OSA assessment, future studies with repeated CRP measurements are warranted to confirm these prospective associations.