Objective: Acute infection is the most common presentation of children to hospital. A minority of these infections are serious, but early recognition and adequate management are essential. We aimed to develop improved tools to assess children attending ambulatory hospital care, integrating clinical features with point-of-care C reactive protein (CRP). Design: Prospective observational diagnostic study. Setting and patients: 5517 acutely ill children (1 month-16 years) presenting to 106 paediatricians at six outpatient clinics and six emergency departments in Belgium. Index test: Point-of-care CRP alongside vital signs and objective symptoms measurements. Main outcome: Hospital admission for >24 hours with a serious infection <5 days after presentation. Results: An algorithm was developed consisting of clinical features and CRP. This achieved 97.1% (95% CI 94.3% to 98.7%) sensitivity and 99.6% (95% CI 99.2% to 99.8%) negative predictive value, excluding serious infections in 36.4% of children. It stratifies patients into three groups based on CRP level: high-risk group with CRP >75 mg/L (26.8% risk of infection), intermediate-risk group with CRP 20-75 mg/L and at least one of seven clinical features (8.1%), and lower risk group with CRP <20 mg/L with at least one of the 11 features (3.8%). Children in intermediate-risk or low-risk groups with normal clinical assessment have 0.6% and 0.4% risk of serious infections, respectively. Conclusions: Conducting a CRP test may first enable children to be stratified into three risk groups, guiding assessment of clinical features that could be performed by junior doctors or nurses. In one-third of acutely ill children, the algorithm could exclude serious infection. Prospective validation of the algorithm is needed.