PURPOSE: The use of prophylactic antibiotics in elective colorectal surgery is essential. Although postoperative prophylactic antibiotics are recommended within 24 hr, the optimal duration of the use of prophylactic antibiotics after colorectal surgery has not yet been fully proven in Korea. The aim of this study was to compare infectious outcomes in elective colorectal cancer surgery between postoperative 3-day antibiotic therapy and 5-day therapy. METHODS: We conducted a multicenter, randomized trial of a 3-day use vs. a 5-day use of the second-generation cephalosporin cefotetan after elective colorectal surgery. The main outcome measures were the incidences of surgical site infection and all other infectious complications within 21 days after surgery. RESULTS: A total of 306 patients were enrolled. Fifty-one patients were excluded because they received additional surgery or dropped out during the study. Two-hundred fifty-five patients were analyzed in this study. The two groups were similar in terms of demographics, ASA score, tumor location, tumor stage, surgical approach (conventional open vs. laparoscopy-assisted vs. robotic-assisted), and type of operation. The incidences of surgical site infection were not significantly different between the 3-day use group (4/130 or 3.1%) and the 5-day use group (3/125 or 2.4%) (P=1.000). Incidences of overall infectious diseases did not differ significantly between the two groups. Postoperatively, both groups had similar values in their white blood cell count, absolute neutrophil count, and C-reactive protein levels. However, the number of patients is small to draw a definite conclusion in this study. CONCLUSION: Three-day cefotetan administration may be not inferior in preventing surgical site infection compared to 5-day antibiotic administration. However, further studies with a large number of patients are needed before a definite conclusion can be drawn.