Context: The literature provides limited evidence of the quality of life (QoL) distinctions between Saudi Arabian male and female patients with sickle cell disease (SCD). Objectives: To compare SCD complications, symptoms, and individual items in the Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36) between Saudi adult males and females. Methods: A multi-center, cross-sectional study was conducted on 629 Saudi adults with SCD who attended King Fahad Hospital in Hofuf and King Fahad Central Hospital in Jazan. Results: Gender differences were noted in terms of SCD-related complications, symptoms, daily activity, and pain. Saudi females with SCD reported significantly more fever (66.8% vs. 54.8%, P=0.003), more swelling (59.2% vs. 38.9%, P=0.001), and more frequent blood transfusion (88.5% vs. 80.6%, P=0.009). Males reported more physical exercising than females (41% vs. 23%, P=0.001), and having less family support (89.6% vs. 96.3%, P=0.001). Saudi females with SCD reported significantly higher percentages of daily activity limitations in lifting or carrying groceries (66.7% vs. 58%, P=0.031), climbing one flight of stairs (63.5% vs. 53.6%, P=0.016), and walking the length of one block (59.2% vs. 42.5%, P=0.001). Saudi females with SCD reported a higher percentage of bodily pain (94.3% vs. 87.1%, P=0.004). Conclusion: The study reveals that Saudi females with SCD experience SCD-related complications, symptoms, and pain differently than Saudi males with SCD. According to our data, females reported more limitations in daily activity, more pain, and less physical activity, than males. An interventional program is needed to address QoL among Saudi females with SCD.