OBJECTIVE: This study evaluates the cost-effectiveness of four antimicrobial regimens (e.g., levofloxacin monotherapy, ceftriaxone monotherapy, ceftriaxone plus a macrolide, and ceftriaxone plus levofloxacin) for the treatment of patients admitted to the medical floor with class IV or V community-acquired pneumonia (CAP). METHODS: All adult patients with a principal discharge diagnosis of pneumonia, admitted to Baptist-Health System from November 1, 1999 to April 30, 2000 were evaluated. Medical floor patients who met criteria for Pneumonia Severity Index (PSI) risk class IV or V were included in this analysis. Total hospital charges were converted to costs using the hospital cost-to-charge ratio. Wilcoxon Rank Sum was used to evaluate associations between antimicrobials received (independent variable) and total hospital cost (dependent variable). Cost-effectiveness ratios were determined by dividing the total hospital cost by the percent survival. RESULTS: A total of 649 patients were managed on the medical floor with 415 (64%) meeting the criteria for PSI risk class IV (N = 274) or V (N = 141) CAP. Costs (median, 25th and 75th quartile) were as follows: total hospital cost ($4,087 [$2,590 - $6,554]), pharmacy costs ($606 [$366 - $1,092]), and antibiotic costs ($112 [$66 - $184]). Total hospital costs were lowest for levofloxacin monotherapy (N = 151, $3,506 [$2,231 - $5,870]), followed by ceftriaxone monotherapy (N = 61, $3,758 [$2,741 - $6,071]), ceftriaxone plus a macrolide (N = 61, $4,163 [$3,100 - $5,726]), and ceftriaxone plus levofloxacin (N = 38, $4,830 [$2,934 - $7,393]) (P = 0.0921). Survival was the highest for patients who received ceftriaxone plus a macrolide (98%), followed by ceftriaxone plus levofloxacin (95%), levofloxacin monotherapy (94%), and ceftriaxone monotherapy (87%) (P = 0.0734). The most favorable cost-effectiveness ratio was observed for patients who received levofloxacin monotherapy ($3,730 per expected cure), followed by ceftriaxone plus a macrolide ($4248), ceftriaxone monotherapy ($4370), and ceftriaxone plus levofloxacin ($5367). CONCLUSION: Among patients admitted to the medical floor for class IV or V CAP, levofloxacin monotherapy is the most cost-effective antimicrobial regimen.