The present study was set out to explore the association among self-report happiness, personality traits and self-esteem in the Greek cultural setting. In particular, it was examined the mediating role of self-esteem on the relation of extraversion, neuroticism and happiness. In the study participated 207 Greek adults aged 25-60 years old. Three different questionnaires were administered to all participants: the Oxford Happiness Questionnaire (OHQ), the Eysenck Personality Questionnaire Revised-Abbreviated (EPQR-A) and the Rosenberg Self-esteem Scale (RSE). Results indicated that the three constructs (self-esteem and two personality traits) jointly explained the 67% of happiness variability. Happiness is best predicted by self-esteem, following by neuroticism (negatively) and extraversion (positively). Moreover, structural equation model (SEM) analysis showed that self-esteem only partially mediated the effects of both extroversion and neuroticism on self-report happiness.