To reduce the incidence of surgical site infection (SSI), perioperative antimicrobial prophylaxis has long been advocated for joint replacement and open reduction with internal fixation of long bones. Increasing health care costs have focused hospital interest on more cost-effective procedures. Although current literature indicates that single-dose antibiotic prophylaxis is comparable to a 3-dose regimen, there are no reports from lowincome countries. The primary aim of this study was to compare the infection rate following open reduction and internal fixation of long-bone fractures in groups with a single dose and 3 doses of prophylactic antibiotic. The secondary aim was to compare the costeffectiveness of both antibiotic regimens. This is a prospective randomized clinical trial (RCT) to compare the incidence of surgical site infection between the patients allocated randomly into two groups with different antibiotic prophylactic regimens: single dose or 3 doses 8 hourly of 1g ceftriaxone administered intravenously. 200 consecutive patients who underwent open reduction and internal fixation (ORIF) for closed long-bone fractures were enrolled in this study. The rate of postoperative SSI was 4.1% in the single-dose group and 2.2% in the 3-dose group; the overall SSI rate was 3.2%. The primary endpoint of this study, which is the incidence of SSI, showed no significant difference between the single-dose and 3-dose prophylactic antibiotic groups. Furthermore, there was no difference between groups regarding the length of hospital stay. Our randomized clinical trial affirmed that single-dose antibiotic prophylaxis in orthopaedic clean operations is not only a cost-saving practice but also is effective for SSI prevention, and should be incorporated in the development of clinical practice guidelines in tropical hospitals.