This study aimed to compare the short-term outcomes of single-access laparoscopic cholecystectomy (SALC) and conventional laparoscopic cholecystectomy (CLC). In a prospective study, patients with symptomatic cholelithiasis were randomized to SALC or CLC with follow-up at 1 week, 1 and 6 months. The primary end point of this study was to assess the total outcomes of quality of life using the EuroQoL EQ-5D questionnaire. The secondary end points were postoperative pain, analgesia requirement and duration of use, operative time, perioperative complications, estimated blood loss, hospital stay, cosmesis outcome, and number of days required to return to normal activities. A total of 269 patients were prospectively randomized into two groups (125 in each group after excluding 19 patients for various reasons). The SALC procedure was done safely without intraoperative or major postoperative complications. In four SALC patients, an extra epigastric port was inserted to enhance exposure. There was no open conversion in either group. SALC patients reported better results among four of the EuroQoL EQ-5D dimensions (mobility, self-care, activity, and pain/discomfort) at 1 week after surgery, an improved pain profile at 4, 12, and 24 h, better cosmetic outcome at 1 and 6 months (P ≤ 0.01), shorter duration of need for analgesia (P ≤ 0.02), and earlier return to normal activities (P ≤ 0.026). Operative times, hospital stay, QOL at 1 and 6 months postoperatively, and estimated blood loss were similar for both procedures. This study supports other studies that show that SALC is a feasible and promising alternative to traditional laparoscopic cholecystectomy in selected patients with better cosmesis, QOL, and improved postoperative pain results, and it can be performed with the existing laparoscopic instruments.