Purpose Personality traits are rather stable dispositions inadulthood, while self-efficacy and adherence may bemodified through targeted interventions. Health-relatedquality of life (HRQL) serves as a vital outcome measure.The present aim was to explore the function of self-efficacyand adherence as mediators for the influencing effect ofpersonality traits on HRQL in people with chronic disease.Methods An epidemiological sample of 786 personscompleted questionnaires on personality, general self-efficacy,adherence behaviour and HRQL. Data were statisticallyanalysed using descriptive statistics, correlationanalyses and path models.Results Self-efficacy mediated the effect of Extraversionand Conscientiousness on mental HRQL. Neuroticism hada direct effect on both physical and mental HRQL.Adherence partially mediated the effect of both Agreeablenessand Conscientiousness on mental HRQL.Conclusions The mental HRQL in people scoring low onExtraversion or low on Conscientiousness could beimproved by strengthening general self-efficacy. Increasingadherence in people scoring low on Agreeableness orConscientiousness could improve their mental HRQL, butthe improvement was small and may be of lesser clinicalrelevance. These results argue for personalized interventionsintended to positively affect health outcomes inpeople with chronic disease.