The objectives of this study were to determine the magnitude of psychiatric disorders and to define socio-demographic and disease-related risk factors in a sample of adolescents with SCD in Al-Hassa, Saudi Arabia. The sample consisted of 110 adolescents with SCD and a convenient sample of 202 adolescents without SCD as controls. Psychiatric assessment was based a double test strategy through employing the observation form of the semi-structured clinical interview for children and adolescents (SCICA), followed by clinical interview based on the Diagnostic and Statistical manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR 2000). The study revealed that 29.0% of adolescents with SCD and 32.0% of adolescents without SCD were screened positive for one or more psychiatric disorders. Adolescents with SCD showed higher prevalence of adjustment and anxiety disorders compared to their peers. Hierarchical logistic regression analysis for determination of the independent predictors of psychopathology among adolescents with SCD revealed that male gender and high family income were independent protective factors while frequent pain episodes served as an independent risk factor for the development of psychiatric morbidity. Psychiatric assessment using a semi-structured clinical interview in adolescents yields a comprehensive view of the adolescent psychopathology in SCD that calls for early identification and intervention.