A work environment characterized by frequent emotionally-charged interactions increases the risk of staff burnout. It was hypothesized that gender differences in psychopathology in forensic mental health settings may be associated with differences in the risk of burnout. The development of single-sex accommodation in a medium secure facility provided an opportunity to examine the impact of such patient gender differences within a therapeutic setting. In this study, nurses allocated to work on a new women's ward were assessed for burnout before the ward opened and a subgroup was re-assessed 18 months later. A comparison group of nurses working on a men's ward were assessed at the same two time points. Nurses working on the women's ward experienced a significantly greater increase in the emotional exhaustion component of burnout. There was some indication of a similar process for the depersonalization component. The implications of these findings are discussed in the context of the literature relating to the psychopathological and interpersonal differences between male and female patients and relating to the responses of clinicians to these differences.