OBJECTIVE To compare the efficacy and safety of intramuscular cefoperazone and intramuscular ceftriaxone in the treatment of nursing home-acquired pneumonia in the nursing home setting. METHODS A randomized clinical trial. METHODS Skilled nursing wards at the Veterans Home of California. METHODS 104 residents of skilled nursing wards, aged 65 years or older. METHODS Intramuscular administration of either cefoperazone or ceftriaxone. METHODS The variables analyzed for baseline comparability were demographics (age, sex), clinical variables (duration in nursing home; presence of sputum, fever, cough, or leukocyte count), and clinical symptoms and signs. Efficacy was assessed by days of therapy, final maximum temperature, and clinical and bacteriological response. RESULTS Fifty residents received cefoperazone, 1 gm every 12 hours, intramuscularly. Fifty-four residents received ceftriaxone, 1 gm every 24 hours, intramuscularly. The total duration of treatment was scheduled for 10 days. Clinical cure was seen in 45 (90%) of the cefoperazone treatment group and 51 (94%) of the ceftriaxone treatment group, with a mean duration of therapy of 10.30 and 9.90 days, respectively. Satisfactory sputum specimens were collected in 71% of the treated residents; the most common isolate was Streptococcus pneumoniae, followed by Haemophilus influenzae and Staphylococcus aureus, respectively. The overall mortality was 4.5% at long-term follow-up. Both agents were well tolerated and no therapy was discontinued due to intramuscular pain or abnormal laboratory values. CONCLUSIONS Intramuscular cefoperazone and intramuscular ceftriaxone are safe and effective in the treatment of nursing home-acquired pneumonia. The clinical outcomes in both treatment groups support their use within this select population without the need for transferring the patient to an acute care hospital. Clinical studies are needed to evaluate the impact of such therapy on the control of health care expenditures within the nursing home facility.