Objective: To compare short-term surgical outcomes and quality of life (QOL) between single-port laparoscopic cholecystectomy (SPLC) and classic 4-port laparoscopic cholecystectomy (CLC). Background: There is significant interest in further reducing the trauma associated with surgical procedures. Although a number of observational studies have suggested that SPLC is a feasible alternative to CLC, there is a lack of data from randomized studies validating any benefit over CLC. Methods: Eligible patients were randomized to receive SPLC or CLC. Operative and perioperative outcomes, including cosmesis and QOL were analyzed. Results: Forty-three patients were randomized to SPLC (n = 21) or CLC (n = 22). There were no significant differences between groups for most preoperative demographics, American Society of Anesthesiology score, gallstone characteristics, local inflammation, blood loss, or length of stay. Patients undergoing SPLC were older than those receiving CLC (57.3 years vs. 45.8 years, P < 0.05). Operative times for SPLC were greater than CLC (88.5 minutes vs. 44.8 minutes, P < 0.05). Overall and cosmetic satisfaction, QOL as determined by the SF-36 survey, postoperative complications, and post-operative pain scores between discharge and 2-week postoperative visit were not significantly different between groups. Wound infection rates were similar in both groups. The SPLC group contained 1 retained bile duct stone, 1-port site hernia, and 1 postoperative port site hemorrhage. Conclusions: SPLC procedure time was longer and incurred more complications than CLC without significant benefits in patient satisfaction, postoperative pain and QOL. SPLC may be offered in carefully selected patients. Larger randomized trials performed later in the learning curve with SPLC may identify more subtle advantages of one method over another.