OBJECTIVE To determine the prevalence of, and factors associated with, depression among sickle cell anemia adult patients in the Eastern Province of Saudi Arabia. METHODS A cross-sectional study was conducted between December 2014 and May 2015 among sickle cell anemia patients aged 16-70 years from the outpatient hematology clinics at Qatif Central Hospital. A total of 110 successive participants consented and answered an anonymous, self-administered, questionnaire and the Arabic version of the Beck Depression Inventory-II. Individuals were considered depressed if they scored ≥14 in Beck Depression Inventory-II. Simple logistic regression was used to compare differences between the depressed and nondepressed groups. Odds ratios (ORs) with 95% confidence intervals (95% CI) were reported. RESULTS Depression was detected in 53 participants (48.2%). Bivariate analysis showed that lower educational qualification (OR = 2.5; 95% CI = 1.1-5.3; P = 0.021), higher frequency of vaso-occlusive crises (OR = 3.4; 95% CI = 1.3-8.7; P = 0.008) and frequent visits to the hematology clinic (OR = 5.3; 95% CI = 1.4-19.9; P = 0.008) were significantly associated with depression. CONCLUSIONS This study revealed that there is high prevalence of depression among sickle cell anemia patients in the Eastern Province of Saudi Arabia.