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Inadequate antibacterial therapy has been associated with increased mortality in severe sepsis and septic shock. The aim of this study was to evaluate the appropriateness of antibiotics in sepsis patients to determine best empirical regimen. Prospective surveillance of 239 septic episodes (223 patients; 261 isolates).Pathogens differed significantly between (1) community- and hospital-acquired sepsis and (2) primary infection sites. In community-acquired infections Gram-negative microorganisms (62/101; 61%) prevailed due to the urinary tract origin of sepsis (33/100; 33%). Carbapenems (95%), piperacillin/tazobactam (89%), ceftazidime (85%), and moxifloxacin (81%) showed in-vitro activities >80%. In hospital-acquired infections, Gram-positive microorganisms (96/160; 60%) dominated due to catheter-related infections (60/139; 43%). None of the tested antibiotics exceeded a susceptibility rate of 66%, thus a combination therapy might be prudent. Community vs. hospital onset of sepsis along with the primary infection site seem to be important enabling better prediction of appropriateness of initial empirical antimicrobial regimen.