Existential issues often accompany a diagnosis of cancer and remain one aspect of psychosocial oncology care for which there is a need for focused, empirically tested interventions. This study examined the efficacy of a novel psychological intervention specifically designed to address existential issues through the use of meaning-making coping strategies on psychological adjustment to cancer. Eighty-two breast or colorectal cancer patients were randomly chosen to receive routine care (control group) or up to four sessions that explored the meaning of the emotional responses and cognitive appraisals of each individual's cancer experience within the context of past life events and future goals (experimental group). This paper reports the results from 74 patients who completed and returned pre- and post-test measures for self-esteem, optimism, and self-efficacy. After controlling for baseline scores, the experimental group participants demonstrated significantly higher levels of self-esteem, optimism, and self-efficacy compared to the control group. The results are discussed in light of the theoretical and clinical implications of meaning-making coping in the context of stress and illness.