The diagnosis of severe bacterial infection in young infants in developing countries is difficult because of the lack of sensitivity and specificity of the presenting symptoms and signs. Whether C-reactive protein (CRP) might help with the early detection of neonatal sepsis was investigated in a prospective study in The Gambia, Ethiopia and The Philippines. Infants < 3 months of age with symptoms or signs of possible sepsis were evaluated; CRP was measured and assessed for its ability to predict proven invasive bacterial infection. Of 966 children < 3 months of age, 54 had a positive blood culture, 13 a positive CSF culture, 15 a positive blood and CSF culture and 884 had negative cultures. Median (interquartile range) CRP values were 42 (9-173), 14 (6-36), 209 (135-286) and 8 (3-27) mg/L in the four groups, respectively. Taking a CRP cut-off of 10 mg/L, the sensitivity and specificity of an elevated CRP to predict a positive blood or CSF culture were 77% and 55%, respectively, and 55% and 82%, respectively, for a cut-off of 40 mg/L. CRP lacks the sensitivity and specificity to be used alone as a predictor of serious infections in young infants.