Background Cholelithiasis (gallstone disease) is found in more than one-half of the patients with sickle cell disease (SCD) by the age of 30 years. Complications of symptomatic cholelithiasis may precipitate to recurrent sickle cell crises, which add to the disease morbidity. Laparoscopic cholecystectomy (LC) is the treatment of choice in patients with symptomatic disease, but the best option for asymptomatic ones is still a source of debate. Aim To compare the outcome of LC in asymptomatic and symptomatic cholelithiasis in patients with SCD. Patients and methods The study was performed on 42 patients with SCD having cholelithiasis. A total of 30 (72%) patients with asymptomatic cholelithiasis underwent prophylactic LC and were compared with those [12 (28%) patients] who were operated owing to symptomatic cholelithiasis. Results The percentage of cholelithiasis was significantly higher in the 12–30 years age group (69%) than in the age groups younger than 12 years and over 30 years (P=0.013). Nine of the 12 (75%) symptomatic patients required emergency cholecystectomy. The mean time of LC procedure and the mean postoperative hospital stay were significantly longer in symptomatic patients when compared with asymptomatic patients (P=0.01 and 0.02, respectively). After LC, a significant reduction in hospital admission rates compared with the rate of admissions during the period before the operation was observed in both groups of patients. Conclusion Elective (prophylactic) LC is recommended to patients with SCD having asymptomatic cholelithiasis because waiting for the appearance of symptoms worsens the postoperative outcome.