receiving treatment for tuberculosis in Soweto, South Africa. A composite diagnostic standard for Streptococcus pneumoniae was considered positive if any of routine blood culture, good quality sputum culture or Gram stain, urinary immunochromatographic testing (ICT) for pneumococcal C-polysaccharide (Binax® Now) or lytA real-time (rt) PCR on blood were positive for pneumococcus or lytA rtPCR on NPS was ≥8000 copies/ml. Other bacterial aetiologies were identified by routine blood cultures and sputum cultures, mycobacterium tuberculosis (TB) was assessed by acid-fast staining of sputum. Multiplex rtPCR for respiratory viruses and atypical bacterial pathogens (Fast-track diagnostics Respiratory pathogens plus) was used on NPA and triplex rtPCR for S. pneumoniae, Staphylococcus aureus and Haemophilus influenzae from whole blood.Results: Among 280 HIV-infected persons with CAP, pneumococcus was the most frequently identified organism (n = 151 [53.9%], of which 79 [28.2%] were monoinfections; 75 [26.8%] by molecular diagnostics only), followed by TB (n = 69 [24.6%], of which 39 [13.9%] were monoinfections). 48 (17.1%) viral or mycoplasma infections were identified (10 as monoinfections, 38 as combinations mostly with pneumococcus [n = 32]). Staphylococcus aureus and Haemophilus influenzae were frequently detected in the nasopharynx, but only rarely isolated from blood or sputum cultures. Up to 5 different organisms were simultaneously present. No aetiology was identified in 22.9% of patients.Conclusion: Using a combination of traditional and molecular methods, an infectious aetiology could be identified in the majority of episodes of acute CAP in HIV-infected South African adults. A large proportion was attributable to polymicrobial infections, most of which included the pneumococcus or tuberculosis. Viral monoinfections were relatively infrequent. Further work is necessary to delineate the utility of bacterial or viral identification from nasopharyngeal specimens as diagnostic tools in CAP.http://dx.