Introduction and Background: Sickle cell disease (SCD) is an extremely challenging disease of global concern. The highest prevalence of SCD in Saudi Arabia is in the Eastern province. Compared to all other areas of Saudi Arabia, Al-Qatif area has the highest gene frequencies for HbS and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency genes. Objective: The objective of this study was to assess the knowledge and misconceptions about SCD of adults (≥18 years) with sickle cell anemia in Al-Qatif area, Eastern Province, Saudi Arabia, and study factors that may affect them. Materials and Methods: A cross-sectional study using a selfadministered questionnaire was distributed to 320 patients aged ≥18 years with sickle cell anemia, who attend the medical outpatient clinics in Qatif central hospital and primary care centers in the Qatif area, Eastern Province, Saudi Arabia. Result: A total of 300 participants completed their questionnaire. In general, 56.3% had poor knowledge of the disease. About 58.3% had good knowledge of the genetic transmission. The knowledge of 46.7% about the precipitating factors was poor. Moreover, 59.3% had poor knowledge of the diet of people with SCD and 81.3% had poor knowledge of the diet of people with G-6-PD deficiency. Conclusion: Our study revealed significant widespread misconceptions of patients with sickle cell anemia especially relating to their diet.