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To investigate the antemortem prevalence and outcome of cytomegalovirus (CMV)-associated pneumonia in African children.A total of 202 children (median age, 3.2 months; 124 human immunodeficiency virus [HIV]-infected, 62%; 87 severely malnourished, 43%) sequentially hospitalized for severe pneumonia were prospectively investigated. In addition to routine microbiologic investigations, respiratory tract secretions and blood were submitted for CMV culture and qualitative and quantitative CMV polymerase chain reaction.CMV-associated pneumonia was common (28%, 47/169) and more prevalent in HIV-infected than uninfected children (36% vs. 15%; odds ratio [OR], 3.0; 95% confidence interval, 1.3–7.4). CMV-associated pneumonia was more common than Pneumocystis pneumonia (27%) and other viral-associated pneumonia (19%) in HIV-infected children. In-hospital mortality was 25% (51/202) with increased mortality in HIV-infected compared with uninfected children (43/124 [35%] vs. 8/76 [11%]; OR, 4.5; 1.9–11.8). Increased mortality occurred in HIV-infected children with CMV-associated pneumonia (OR, 2.5; 1.04–6.5) but this association was not evident after adjusting for CD4 <15% (adjusted OR, 1.78; 0.6–4.6).CMV-associated pneumonia is common and associated with a poor outcome in children with advanced HIV disease. Improved diagnostic testing and increased access to antiviral therapy might improve the outcome of HIV-infected children with CMV-associated pneumonia.