Background: Sub-Saharan Africa is home to a large population of HIV-infected and HIV-exposed, -uninfected (HEU) children that are at risk for severe pneumonia attributed to opportunistic infections, including human cytomegalovirus (CMV). The role of CMV in pneumonia etiopathogenesis amongst these children is disputed, however. Methods & Materials: We evaluated whole blood CMV viral load using PCR in South African children enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case–control study. Cases, 1–59 months of age hospitalized with World Health Organization-defined severe/very severe pneumonia, were matched by age and season to community controls. A composite measure of disease severity was derived for children with radiologically-confirmed pneumonia that had high-density nasopharyngeal CMV carriage and were either mechanically ventilated, hospitalised for >5 days, or died. CMV viral load on whole blood was compared between cases with severe-composite disease, all other cases and controls. Results: Cut-off densities of 3.33, 2.53 and 2.69 log10 copies/mL of CMV in whole blood, respectively, discriminated between HIV-unexposed, HEU and HIV-infected cases with radiologically-confirmed pneumonia and age-, season-matched controls. HIV-unexposed, HEU and HIV-infected children with severe composite disease were significantly younger (HIV-unexposed: 5.5 vs 6.0 vs 7.0 months; HEU: 4.0 vs 5.0 vs 9.0 months; HIV-infected: 5.5 vs 8.0 vs 9.5 months) and severely underweight (HIV-unexposed: 32.6% vs 8.7% vs 0.9%; HEU: 35.0% vs 14.4% vs 2.3%; HIV-infected: 30.4% vs 33.8% vs 12.6%) compared to all other cases and controls. CMV whole blood PCR discriminated between cases with severe-composite disease and all other cases in the HEU (adjusted odds ratio (aOR), 2.32; 95% CI, 1.09–4.91) and HIV-infected (aOR, 2.71; 95% CI, 1.15–6.39) groups. Additionally, CMV whole blood PCR discriminated between cases with severe-composite disease and controls in HIV-unexposed (aOR, 4.04; 95% CI, 1.59–10.25), HEU (aOR, 6.60; 95% CI, 1.31–33.31) and HIV-infected children (aOR, 10.29; 95% CI, 2.81–37.65). Conclusion: In African children <5 years of age hospitalized for severe community-acquired pneumonia, CMV detection in whole blood PCR discriminated between severe-composite disease and all other cases in HEU and HIV-infected patients. The test may guide choice of therapy in a select group of immunocompromised cases in whom a diagnosis of CMV pneumonia is being considered.