Staphylococcus aureus and beta-hemolytic streptococci (BHS) are the 2 main types of bacteria causing soft-tissue infections. Historically, BHS were believed to be the primary cause of diffuse, nonculturable cellulitis. However, with the recent epidemic of community-associated methicillin-resistant S aureus (MRSA) causing culturable soft-tissue infections, it is currently unclear what role either of these bacteria has in cases where the cellulitis is diffuse and nonculturable. This uncertainty has led to broad-spectrum and haphazard use of antibiotics for this infection type, which has led to increased risk of adverse drug reactions, health care costs, and emergence of resistance in bacteria. To investigate this issue, we conducted a prospective investigation between December 2004 and June 2007, enrolling all adult patients admitted to the inpatient service at the Olive View-UCLA Medical Center, a county hospital of Los Angeles, with diffuse, nonculturable cellulitis. Acute and convalescent serologies for anti-streptolysin-O and anti-DNase-B antibodies were obtained. Patient data were analyzed for response to beta-lactam antibiotics. The primary outcome was the proportion of these cases caused by BHS, as diagnosed by serologies and/or blood cultures, and the secondary outcome was the response rate of patients to beta-lactam antibiotics. Of 248 patients enrolled, 69 were dropped from analysis because of loss to follow-up or exclusion criteria. Of the 179 remaining patients, 73% of nonculturable cellulitis cases were caused by BHS. Analysis of outcomes to beta-lactam antibiotic treatment revealed that patients diagnosed with BHS had a 97% (71/73) response, while those who did not have BHS had a 91% (21/23) response, with an overall response rate of 95.8% (116/121). Results of this large, prospective study show that diffuse, nonculturable cellulitis is still mainly caused by BHS, despite the MRSA epidemic, and that for this infection type, treatment with beta-lactam antibiotics is still effective. A cost-effective, evidence-based algorithm can be useful for the empiric management of uncomplicated soft-tissue infections based on the presence or absence of a culturable source.