Background. Although there is considerable support for adverse relationships between states of psychological and somatic distress and immune response, there is little evidence in humans of the relative contribution of genetic and environmental factors. Methods. This study utilized a twin methodology to examine the interplay between psychological distress, fatigue and immune function. We recorded a number of measures of distress, including conventional depression and anxiety as well as the somatic symptom of prolonged fatigue, and immune responsiveness (by delayed-type hypersensitivity skin response) in 124 normal adult twin pairs (79 monozygotic, 45 dizygotic). Results. While there were strong genetic influences on the psychological distress and fatigue factors (only some of which are common to both), familial aggregation of immune responsiveness arose mainly from environmental factors shared by both members of a twin pair. Phenotypic correlations between psychological and immune measures were negligible, but multivariate genetic modelling revealed that these masked larger genetic and environmental correlations of opposite sign. Negative environmental effects of psychological distress and fatigue on immune responsiveness were countered by a positive genetic relationship between psychological distress and immune function. Conclusions. Our study suggests that current psychoneuroimmunological hypotheses in humans need to be modified to place increasing importance on the individual's genotype. In this cohort immune responsiveness varied in response to a complex interplay of genetic and environmental factors. Additionally, although psychological distress and fatigue had some shared genetic determinants, independent genetic and environmental risk factors for fatigue were also identified.