Background: While mental workload and stress among nurses are generally well-documented, differences within the nursing profession have hardly been investigated so far. Aim: This study aims to examine the differences and associations between psychosocial working conditions and symptoms of burnout of nurses working in somatic and psychiatric settings. Methods: A cross-sectional study has been conducted with employees in one somatic and one psychiatric hospital (n = 576). The Copenhagen Psychosocial Questionnaire and the Copenhagen Burnout Inventory were used to assess psychosocial workloads and burnout symptoms. The data analysis was carried out by univariate, bivariate and multivariate (regression) analyses. Results: About 50 % of respondents report at least a moderate level of symptoms of burnout with somatic nurses more frequently affected. While quantitative and physical demands are higher in somatic nursing, psychiatric nurses have a higher degree of emotional demands, socialβ = 0.33) in somatic nursing and emotional demands (β = 0.29) in psychiatric nursing serve as strongest predictors of burnout symptoms. Conclusions: Findings suggest specific profiles of psychosocial workload in somatic and psychiatric nursing as well as a high need for differentiated approaches for occupational health promotion.