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Cardiovascular disease (CVD) is the world's most prevalent chronic disease and the leading chronic cause of morbidity. There are several psychosocial factors associated with quality of life during CVD. Our main objectives were to analyze the roles of conscientiousness, subjective wellbeing and self-efficacy beliefs. The sample comprised 514 patients (mean age 63.57 years) who were assessed twice over a nine-month interval. At Time 1, participants answered a questionnaire assessing conscientiousness, perceived subjective wellbeing (positive and negative affect, life satisfaction), cardiac self-efficacy and health-related quality of life (HRQoL). The same variables (except for conscientiousness) were re-assessed at Time 2. Results showed that conscientiousness had a positive relation with subjective wellbeing, cardiac self-efficacy, and HRQoL at Time 1. Moreover, cardiac self-efficacy at Time 1 had a positive longitudinal effect on HRQoL at Time 2, while controlling for autoregressive effects. Mediation analyses indicated that the relationship between conscientiousness and HRQoL was mediated by positive affect and cardiac self-efficacy. These results suggest the usefulness of psychosocial interventions aimed at promoting positive affect and self-efficacy beliefs among CVD patients.