BACKGROUND: Rapid means of ruling in or ruling out tuberculosis (TB) would permit more efficient management of patients starting antiretroviral treatment (ART). OBJECTIVE: To assess the diagnostic and prognostic utility of C-reactive protein (CRP) among patients being screened for TB before ART in a South African ART clinic. DESIGN: Patients were microbiologically screened for TB regardless of symptoms; serum CRP was measured, and mortality at 3 months was assessed. RESULTS: Among 496 patients (median CD4 count 171 cells/l), culture-positive TB was diagnosed in 81 (16.3%). CRP concentrations were much higher among TB cases (median 57.8 mg/l, IQR 20.0202.7) than in those without TB (6.4 mg/l, IQR 2.121.8, P < 0.001). Very low (<1.5 mg/l) CRP concentrations excluded TB (100% negative predictive value), whereas very high concentrations (>400 mg/l) were strongly predictive of TB (100% positive predictive value). However, these thresholds encompassed only 14.3% and 2.0%, respectively, of all patients screened and identified only 12.3% of TB cases. CRP concentrations ≥50 mg/l were associated with poor prognostic characteristics, higher mycobacterial load, disseminated disease and greater mortality risk. CONCLUSION: CRP concentrations identified groups of patients with very high or very low TB risk, but only in an unacceptably small minority of patients screened. However, in those with confirmed TB, CRP concentrations had useful prognostic value.