Background: It is unclear how well a C-reactive protein (CRP) value predicts a serious infection (SI) in young febrile children in general practice. Methods: This prospective cohort study with 1-week follow-up included children, aged 3 months to 6 years, presenting with fever to a general practitioner out-of-hours service. We evaluate whether CRP level has predictive value for diagnosing a child at risk for an SI either at presentation or during follow-up. The index test was CRP <= 20 mg/L (rule out an SI) and >80 mg/L (rule in an SI). The reference standard was referral to a pediatric emergency department or diagnosis of an SI. The main outcome measure was CRP value. Results: CRP level was available for 440 children. To rule out an SI, CRP <= 20 mg/L did not change the probability of having no SI (87.5%). CRP >80 mg/L increased the probability of having an SI from 11.4% (pretest probability) to 21.2% (posttest probability). In children without a diagnosis of SI at presentation, CRP could not predict an SI during follow-up (CRP >80 mg/L: positive likelihood ratio, 2.1, 95% confidence interval, 1.3-3.5; CRP <= 20 mg/L: negative likelihood ratio, 0.9, 95% confidence interval, 0.7-1.2). Conclusions: In general practice CRP has little clinically relevant value in discriminating febrile children in need of medical care from those who are not.