Prior research has shown that the personality variables extraversion and neuroticism predict burnout among frontline staff working in residential treatment centers. This study tested the hypothesis that the effect of personality on burnout would be moderated by the psychiatric characteristics of the youth served on the milieu. Two hundred and three frontline staff working in 21 residential treatment centers in Illinois serving troubled youth completed surveys regarding opinions about their jobs, the Big Five Inventory (BFI), a youth presenting problems scale for the entire milieu, and the Maslach Burnout Inventory (MBI). Results indicated that the effect of neuroticism on burnout is moderated by psychosis and posttraumatic stress disorder (PTSD); high and moderate milieu ratings of psychosis and PTSD showed a positive relationship between neurosis and burnout, while low ratings of these conditions showed no relationship. These findings suggest that the optimal work setting is a function of the interaction between specific personality characteristics and specific work environments, with implications for personnel selection and future research on person-environment fit.