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Background and aims: Thalassemia is the most common hereditary chronic anemia in humans. Stress caused by the disease leaves adverse effects on children’s self-efficacy in the care of family members, especially mothers. Therefore, this study aimed to determine the effect of stress management training, self-efficacy in mothers of children with thalassemia. Methods: This quasi-experimental study was conducted in Seyedalshohada hospital (clinic of imam Reza) in Isfahan in 2014. 64 mothers of children with thalassemia were randomly assigned into two experimental and control groups. Demographic questionnaires and researcher-designed questionnaires of parental self-efficacy questionnaires dealing with the disease were completed at the beginning and end of the study and in the follow-up to the control group. Stress management training was conducted for experimental group of 8 sessions weekly. Data were analyzed using SPSS software and statistical tests of Mann-Whitney test, independent t-test and fisher exact test. Results: The results of study showed that there was no significant difference between the experimental and control groups in terms of self-efficacy score before the intervention(P=0.148), but self-efficacy score in the experimental group was significantly more than the control group after intervention as well as a month later, (P=0.001). Generally, self-efficacy in mothers after the intervention and one month later increased in comparison with pre intervention. Conclusion: The results showed that stress management training program can be a useful approach to increase self-efficacy in mothers of children with thalassemia. Therefore, it is recommended to improve the self-efficacy in mothers of children with chronic diseases such as thalassemia.