Abstract This study investigated the effectiveness of a treatment, based on self-regulation theory, to enhance the coping self-efficacy of persons with cancer. The intervention, which is called Mastery Enhancement Therapy (MET), is based on Solution Focused Therapy. MET focuses on mastery experiences to improve the participants’ self-efficacy for coping. The participants, who volunteered for the study, were selected based their less-than-average coping self-efficacy scores and were randomly assigned to a treatment group or a no-treatment control group. The treatment group participants met, individually, for four sessions with one of two therapists. All participants completed measures of coping self-efficacy, depression, adjustment to illness, quality of life, perceived social support, and sickness impact at baseline, after the second session, at post-treatment, and at a 3-month follow-up assessment. Control participants completed the measures at times roughly yoked to the treatment participants. Repeated measures ANCOVA and multilevel modeling indicated that for coping self-efficacy and quality of life, there were some modest benefits for the treatment group. however, the diverging patterns during treatment converged at the 3-month follow-up assessment. The results have implications for self-regulation and resilience theories and the investigation of the natural process of recovery in persons with cancer.