Introduction/Statement of problem. Carisoprodol is an oral muscle relaxant used to treat acute, painful musculoskeletal conditions. The objective of this study was to determine the efficacy and tolerability of carisoprodol 250-mg tablets four times daily compared to carisoprodol 350-mg tablets four times daily and placebo in patients with acute, painful muscle spasm of the lower back. Materials and Methods. This was an IRB-approved, multicenter, double-blind, placebo-controlled study in patients 18 to 65 years of age. Efficacy was assessed by two coprimary variables: (1) patient-rated global impression of change, and (2) patient-rated relief from starting backache, and four secondary variables: (1) the Roland-Morris Disability Questionnaire (RMDQ), (2) time to symptom improvement, (3) patient-rated medication helpfulness, and (4) physician-measured range of motion. A positive outcome required both coprimary endpoints to be significant (P<.025) at Study Day 3. A subgroup analysis was performed to determine if efficacy was dependent on sedation. Results. 806 patients (250-mg, n=264; 350-mg, n=273; placebo, n=269) were analyzed for efficacy. Global impression of change (P=.0046), and patient-rated relief from starting backache (P=.0001) were significantly improved compared to placebo at Day 3 with carisoprodol 250-mg, and there was no significant difference between the 250-mg and 350-mg groups. Moderate or marked symptom improvement occurred significantly (P<.01) earlier with carisoprodol 250-mg (4 days) than with placebo (5 days). Discontinuations from adverse events were more frequent in the carisoprodol 350-mg group (3.9%) than in the carisoprodol 250-mg group (0.7%). Conclusions. This study demonstrated that carisoprodol 250-mg four times daily is effective for treating acute muscle spasm of the lower back, and that efficacy is not dependent on sedation. No significant difference in any of the efficacy variables was observed between the carisoprodol 250-mg and 350-mg groups; however, the 250-mg dosage was better tolerated and resulted in fewer discontinuations due to adverse events.