Key PointsQuestionWhat is the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with sickle cell disease (SCD)?FindingsIn this cross-sectional analysis of 2264 individuals with SCD, 47.8% reported frequent pain (ie, ≥ 4 pain crises in 12 months). Although educational attainment and income were not significantly associated with increased pain episode frequency or severity, age, sex, and depression were associated with SCD-related pain.MeaningPain is complex, and these findings suggest that screening patients with SCD for depression and other mental health challenges is warranted, especially among those experiencing higher pain episode frequency and severity.