This study examined the relationship between humor styles, positive personality (optimism and self-esteem), social support and both subjective and psychological well-being. Structural equation modelling was used with a sample of 468 adults; some had a good health status while others suffered from different medical conditions. The best model is the one that proposes that humor styles were associated with SWB and PWB through personality characteristics and social support. This model indicated that humor styles had an indirect effect on SWB through optimism and an indirect effect on PWB through self-esteem. The component of self-oriented humor explained well-being to a greater extent than the component oriented towards interpersonal relations. However, the relationships between the variables included in the model depended on individual differences in gender and health status. Results showed that self-enhancing humor and self-defeating humor predicted SWB through optimism and predicted PWB through self-esteem and social support for women and healthy individuals. Practical implications of the present findings are discussed.