Background: Point-of-care (POC) C-reactive protein (CRP) testing in the primary healthcare setting is a cost-effective approach for reducing antibiotic prescriptions, but has yet to be widely adopted. Methods: Analytical performance of the cobas CRP Test on the cobas b 101 system was evaluated at three POC sites and one reference laboratory. Within-run (repeatability), within-laboratory (intermediate precision), and between-laboratory precision (reproducibility) were assessed. Method comparison (reference test: CRPNX reagent [cobas c 501 module]) and matrix/lot-to-lot comparison experiments were conducted using prospectively collected blood samples from 217 adults (apparently healthy or with clinically relevant conditions). Usability and reliability were assessed by questionnaire and error reporting. Results: Coefficients of variation (CV) for repeatability and intermediate precision ranged from 1.7%–4.0% and 1.9%–4.5%, respectively, for human serum pools containing CRP 4.7–350.7 mg/L; repeatability in clinical samples ranged from 1.6%–5.9% (3.3–360.3 mg/L). CVs for reproducibility ranged from 2.5%–4.0% (4.7–344.3 mg/L). CRP concentrations were comparable for capillary whole blood, serum, Li-heparin whole blood/plasma, K2 and K3 EDTA whole blood/plasma (Pearson's r ≥ 0.996), and among three CRP Test lots (r ≥ 0.993). Clinically relevant CRP concentrations measured with the CRP Test showed good agreement with those measured by CRPNX reagent (serum, weighted Deming regression y = 0.97× + 0.11; Pearson's r ≥ 0.996). The overall mean usability score was 4.18/5 and the error rate across 9378 tests was 1.00%. Conclusions: The cobas CRP Test on the cobas b 101 system demonstrates robust analytic performance when used by healthcare professionals in the POC setting.