Background: Ertapenem is a new, structurally unique, parenteral beta-lactam antimicrobial agent that can be administered once daily. Objective: This study compared the local tolerability of ertapenem 1 g once a day administered intramuscularly (IM) versus IM ceftriaxone, with both drugs reconstituted in lidocaine. Methods: In this prospective, double-blind, multicenter study, adult patients with lower respiratory tract infection, skin infection, or urinary tract infection requiring initial parenteral therapy were randomly assigned in a 3:1 ratio to treatment with IM ertapenem 1 g once daily or IM ceftriaxone 1 g once daily. Although study drugs were administered by unmasked personnel, the patients, investigators, and the sponsor medical reviewer were blinded. Patients who improved clinically could be switched to oral amoxicillin-clavulanate after at least 2 days of IM therapy. Tolerability and safety analyses were carried out for the treated population, and efficacy analyses were performed for the modified intent-to-treat population. Results: A total of 117 patients were randomized. The 87 patients in the ertapenem group and 30 in the ceftriaxone group received IM therapy for a mean duration of 4.1 and 3.8 days, respectively. During treatment, 35.6% (31/87) of patients treated with ertapenem and 43.3% (13/30) of those treated with ceftriaxone experienced ≥1 symptom at the local injection site; the most common symptom was tenderness, followed by pain. Symptoms were moderate to severe in only 1 patient (1.1%) in the ertapenem group and 3 patients (10.0%) in the ceftriaxone group. Clinical drug-related adverse events were reported during IM therapy in 14 patients (16.1%) in the ertapenem group and 5 patients (16.7%) in the ceftriaxone group. Mean ± SD creatine kinase concentrations, measured in all patients, were 204.8 ± 234.8 U/L at the end of IM ertapenem therapy and 382.9 ± 721.1 U/L at the end of IM ceftriaxone therapy; at follow-up, values had returned to normal or had decreased in all cases. Conclusions: Ertapenem 1 g (reconstituted in lidocaine) administered once daily IM was generally well tolerated. The tolerability and safety profiles of IM ertapenem therapy in this study were comparable to those of IM ceftriaxone therapy.