Abstract  Hopelessness and hostility are linked to progression of carotid atherosclerosis (PCA). The purpose of this study was to replicate such relations and to evaluate the role of biological pathways involving hyperactivation of the sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenocortical (HPA) axis. PCA was evaluated by 4-year change in three ultrasound measures of intima-media thickness (IMT) in 1027 men aged 42–60 years at baseline. Effect modification and mediation of relationships between psychosocial factors and PCA were examined for the measures systolic blood pressure (SBP), fibrinogen, and waist-to-hip ratio (WHR), levels of which are indicative of activity along these pathways. Hopelessness and hostility were associated with PCA. Fibrinogen mediated to a moderate extent the association between hopelessness and PCA. SBP significantly modified the relation between hostility and PCA in participants of moderate hostility. The above biological pathways are implicated in the mechanisms connecting hopelessness, hostility, and PCA.