Malaria infection and septicaemia are major determinants of childhood morbidity and mortality in Nigeria. Both often co-exist. While each has different modality of treatment, clinical differentiation can be difficult. This causes delays in treatment and worsens outcome. This study was conducted to determine the value of serum C-reactive protein in differentiating between malaria, and malaria coexisting with septicaemia in infants and children in Calabar. A total of 292 (151 subjects and 141 age/sex matched healthy controls) children aged 6 - 60 months attending the Children's Emergency Room (CHER) and Child Welfare Clinic (CWC) of the University of Calabar Teaching Hospital (UCTH) were recruited consecutively, into the study, between June and November, 2003. The major groups studied were those with malaria alone, malaria coexisting with septicaemia, and controls. All had their blood samples analysed for serum C-reactive protein (CRP), using high sensitivity CRP enzyme immunoassay (EIA) kit - a product of Kalon Biological Ltd UK. Also, blood culture, total white blood cell count (WBC), erythrocyte sedimentation rate (ESR) and blood films for malaria parasites (thin and thick) were done following standard procedures. Only in the controls were blood culture not done. Out of 151 subjects, 130 (86.1%) had malaria alone while 21 (13.9%) had malaria coexisting with septicaemia with culture isolates of Enterobacteriaceae (7) Staphylococcus aureus (9) Salmonella spp (4) and Streptococcus pneumoniae (1). The mean serum CRP levels in subjects with malaria alone and malaria coexisting with septicaemia were 82.16 ± 44.94mg/l and 108.44 ± 55.65mg/l respectively; while that in controls was 5.58mg/l ± 8.52mg/l. Levels were higher in those with malaria coexisting with septicaemia than in malaria alone. This difference was statistically significant (p=0.0176). Conversely, the mean WBC counts; ESR, and absolute neutrophil count could not differentiate between malaria alone and malaria coexisting with septicaemia (p>0.05). Using a diagnostic level of 90mg/l of CRP (value greater than the mean for subjects with malaria alone) in detecting septicaemia in 21 subjects with malaria coexisting with septicaemia, the sensitivity, specificity, positive and negative predictive values were 76.2%, 36.9%, 16.3% and, 90.5% respectively. The main findings showed that serum CRP was sensitive enough to detect septicemia in children with malaria coexisting with septicaemia. Despite low specificity and positive predictive value, serum CRP has numerous advantages over WBC count, ESR, and absolute neutrophil count such as early rise in infection and inflammatory conditions, cost effectiveness and rapid decrease following successful treatment. Because bacteraemia is rapidly fatal in children if not treated, it is recommended that at CRP levels of ≥ 90mg/l antibiotics should be started. These can be withdrawn in 24 hours when preliminary blood culture result is available.