We reviewed the bibliographic evidence from comparative trials regarding the role of rifampin as adjuvant treatment in the treatment of Gram-positive infections [PubMed (1/1950-7/2006)]. Only studies reporting comparative outcome data in patients treated with an antibiotic regimen with the addition or not of rifampin were included. Eight comparative studies were identified [all were randomized controlled trials (RCTs)], five reporting on infections caused by staphylococci (S. aureus in 97% of patients) and three by streptococci. There was no statistically significant difference in mortality between the treatment arms (with and without rifampin) in any of the included studies. Clinical cure was achieved more commonly (p < 0.05) in the rifampin treatment arm in 3/8 studies; in staphylococcal infections of orthopedic stable implants and in beta-hemolytic streptococcal pharyngitis in children (one RCT each), and in one RCT that reported on patients with various staphylococcal infections. However, no statistically significant difference in cure of the infection between the two groups was found after pooling data from two RCTs (121 patients) that reported on patients with various staphylococcal infections (odds ratio = 0.57; 95% confidence interval 0.27-1.17). No differences were noted between the two groups regarding relapse of infection or adverse events. There is only limited evidence from comparative trials regarding the role of rifampin as adjuvant therapeutic agent for infections caused by Gram-positive bacteria, not allowing for definitive conclusions on this important management question. More controlled trials are necessary for better evaluation of this practice.