Background: Level of stress and its management affects the dimensions of psychosomatic patients′ quality of life (QoL), which is an important psychological issue. The present study aimed to investigate the effect of cognitive behavioral stress management program on psychosomatic patients′ QoL. In cognitive behavioral method, patients discover thought and behavioral mistakes and recover them. The criterion to evaluate the success of the present study was measurement of the patients′ QoL and its notable improvement after intervention. Materials and Methods: This is a before-and-after clinical trial with a control group. The study participants comprised 70 psychosomatic patients referred to subspecial psychiatry clinic in Isfahan who were selected through convenient sampling and allocated to the study and control groups. Quality of Life Questionnaire (SF36) was adopted to collect the data. The questionnaire was completed by the participants in three stages of before-and-after up to a month after intervention. Cognitive behavioral stress management program was administrated in study group for eight straight sessions, two month, and a month after intervention. Along with this, conventional medical treatments were conducted for both the groups. Data were analyzed by ANOVA. The significance level was P < 0.001. Results: There was no significant difference in QoL mean scores between the two groups before intervention (44, 43.1), but mean scores of QoL were significantly higher in intervention G (55.7, 59.1), compared to control (39.8, 35.7), after intervention (P < 0.001) and one month after intervention (P < 0.001). Conclusions: Cognitive behavioral stress management, conducted in the present study, had a notable effect on QoL. Therefore, designing psychological interventions based on cognitive behavioral stress management is suggested as an efficient clinical intervention.