Introduction: Increased peripheral inflammation has been consistently documented in both adult and pediatric depression. However, elevated levels of C-reactive protein (CRP), a nonspecific biomarker for inflammation, have been primarily reported in adults; whether CRP plays a similar role in adolescent depression has not been conclusively established. In our prior work, we identified relationships between CRP and reward neurocircuitry in adolescents with psychiatric symptoms (N = 64) but not with depressive symptoms. Extending this work, we sought to examine CRP across the full range of mood and anxiety symptom severity in a larger, clinically diverse cohort of psychotropic medication-free adolescents and healthy controls (HCs). Methods: Subjects were adolescents (N = 127, age: 15.17 ± 2.19 years, 78 female) with psychiatric symptoms (n = 96, including previous cohort of 64) and HC (n = 31). All completed a semi-structured psychiatric evaluation and dimensional assessments for depression, anxiety, anhedonia, and suicidality. Group-comparison and correlation analyses utilized nonparametric statistics controlled for body mass index, sex, and age at pFWE < 0.05. Results: No group differences were identified in CRP levels between the clinical cohort and HCs. In addition, correlations between CRP and clinical symptomatology were not significant in either the whole sample or the psychiatric group. Conclusions: We found that, unlike in adults, CRP was not associated with depressive symptoms. This suggests that inflammation in pediatric depression is more narrowly delimited at the onset of psychiatric symptoms and may only become systemic with chronicity.