There has been an abundance of research discussing the health implications of generalised trust and happiness over the past two decades. Both attitudes have been touted as independent predictors of morbidity and mortality, with strikingly similar trajectories and biological pathways being hypothesised. To date, however, neither trust nor happiness have been considered simultaneously as predictors of mortality. This study, therefore, aims to investigate the effects of generalised trust and happiness on all-cause and cause-specific mortality. The distinction between different causes of death (i.e. cardiovascular vs. cancer-related mortality) allowed us to assess if psychosocial mechanisms could account for associations between generalised trust, happiness and mortality. The study sample was derived from US General Social Survey data from 1978 to 2010 (response rates ranged from 70 to 82 per cent), and combined with death records from the National Death Index. The analytical sample comprised 23,933 individuals with 5382 validated deaths from all-cause mortality by 2014. Analyses were performed with Cox regression models and competing-risk models. In final models, generalised trust, but not happiness, showed robust and independent associations with all-cause mortality. Regarding cause-specific mortality, trust only showed a significant relationship with cardiovascular mortality. The distinct patterns of association between generalised trust and all-cause/cause-specific mortality suggest that their relationship could be being driven by cardiovascular mortality. In turn, this supports the feasibility of psychosocial pathways as possible biological mechanisms from distrust to mortality.