Occupational stress is a multivariate process involving sources of pressure, psycho-physiological distress, locus of control, work dissatisfaction, depression, anxiety, mental health disorders, hopelessness, and suicide ideation. Healthcare professionals are known for higher rates of occupational-related distress (burnout and compassion fatigue) and higher rates of suicide. The purpose of this study was to explain the relationships between occupational stress and some psychopathological dimensions in a sample of health professionals. We investigated 156 nurses and physicians, 62 males and 94 females, who were administered self-report questionnaires to assess occupational stress [occupational stress inventory (OSI)], temperament (temperament evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire), and hopelessness (Beck hopelessness scale). The best Multiple Indicators Multiple Causes model with five OSI predictors yielded the following results: χ2(9) = 14.47 (p = 0.11); χ2/df = 1.60; comparative fit index = 0.99; root mean square error of approximation = 0.05. This model provided a good fit to the empirical data, showing a strong direct influence of casual variables such as work dissatisfaction, absence of type A behavior, and especially external locus of control, psychological and physiological distress on latent variable psychopathology. Occupational stress is in a complex relationship with temperament and hopelessness and also common among healthcare professionals.