The clergy occupation is unique in its combination of role strains and higher calling, putting clergy mental health at risk. We surveyed all United Methodist clergy in North Carolina, and 95% (n = 1,726) responded, with 38% responding via phone interview. We compared clergy phone interview depression rates, assessed using the Patient Health Questionnaire (PHQ-9), to those of in-person interviews in a representative United States sample that also used the PHQ-9. The clergy depression prevalence was 8.7%, significantly higher than the 5.5% rate of the national sample. We used logistic regression to explain depression, and also anxiety, assessed using the Hospital Anxiety and Depression Scale. As hypothesized by effort-reward imbalance theory, several extrinsic demands (job stress, life unpredictability) and intrinsic demands (guilt about not doing enough work, doubting one's call to ministry) significantly predicted depression and anxiety, as did rewards such as ministry satisfaction and lack of financial stress. The high rate of clergy depression signals the need for preventive policies and programs for clergy. The extrinsic and intrinsic demands and rewards suggest specific actions to improve clergy mental health.