Although religion is usually portrayed as a source of comfort, individuals may also experience strain in their religious lives. Associations between religious variables and psychological distress were examined within two groups: a nonclinical sample of 200 college students and a clinical sample of 54 persons seeking outpatient psychotherapy. Participants reported more comfort than strain associated with religion. Religious strain was associated with greater depression and suicidality, regardless of religiosity levels or the degree of comfort found in religion. Depression was associated with feelings of alienation from God and, among students, with interpersonal conflicts on religious domains. Suicidality was associated with religious fear and guilt, particularly with belief in having committed an unforgivable sin. Religious strain, along with religiosity, was associated with greater interest in addressing religious issues in psychotherapy. These results highlight the role of religious strain as a potentially important indicator of psychological distress.