Rationale and Objectives: Increased levels of high-sensitivity C-reactive protein (CRP) are associated with mood symptoms in adults with bipolar disorder (BD). The few studies on this topic in youth with BD have not included controls. We, therefore, examined CRP levels in relation to symptomatic status in youth with and without BD. Methods: Participants included 154 youth (mean age 17 years; 48 asymptomatic BD, 39 symptomatic BD, 67 healthy controls (HC)). Rank analysis of covariance test examined group differences in CRP, controlling for age and sex. Correlation between CRP and mood symptom severity was examined using Spearman’s correlation within the BD group. Results: There were significant group differences in CRP levels ( F_(2,151) = 5.06, p = 0.007, [Formula: see text]); post hoc analyses showed higher CRP levels in the symptomatic BD group compared with HC ( p = 0.01). In sensitivity analyses, this finding was no longer significant after controlling for body mass index (BMI). CRP was not significantly associated with symptomatic severity. Conclusions: CRP levels are elevated among symptomatic youth with BD, partly related to BMI. As elevated BMI is associated with mood symptom burden, prospective studies are warranted to parse the associations among mood symptoms, BMI, and inflammation. Given the proportion of time that youth with BD are symptomatic, present findings raise concern about the long-term impact of elevated CRP on blood vessels, brain, and related clinical outcomes.