The interaction of optimism, hopelessness and social support as predictors of Health-Related Quality of Life (HRQL) among seriously ill people is not well understood. Also, the impact of partner characteristics on patient quality of life has often been overlooked. In this study the relationships between optimism, hopelessness, partner support and HRQL were investigated in 155 cancer patients and their partners. Special attention was given to the effects of optimism and hopelessness as mediators and moderators in the partner support—HRQL relationship. The impact of partner optimism and hopelessness on perceived partner support and patient HRQL was also studied. The results indicated substantial gender differences in the relationships between the study variables. High levels of partner support were associated with female patients' optimistic appraisals, and together they predicted better HRQL at 8 months follow-up. Partial support was found for the effect of optimism as a mediator. For male patients, low hopelessness was the key variable predicting good HRQL. Clear evidence for the moderator effects of optimism/hopelessness was not found, and the expected impact of partner's characteristics on partner support or patient HRQL could not be confirmed. Although partner support, patient optimism and hopelessness all appeared to be important determinants of HRQL in cancer patients, the relationships between these variables differed by gender. The proposed mediation and moderation models needs to be confirmed in future studies.