The current research aimed to examine the effectiveness of the Mode Deactivation Therapy (MDT) on improving differentiation of self and psychological well-being of patients with HSAN-2. The research design was semi-experimental single case with multiple baselines. The statistical population of the research included 50 patients with HSAN2 all over the world from whom 2 were recruited (one from Iran and one from Canada) using purposive sampling method with inclusion-exclusion criteria. The patients filled out Skowron & Friedlander’s (1998) Differentiation of Self Inventory and Ryff’s (1989) Psychological Well-Being Questionnaire. The data were analyzed using clinical significance, visual inspect, diagnostic improvement and the six indices of efficacy. According to the results, the total percentage of improvement for differentiation of self and psychological well-being were 52.76 and 52.69, respectively. One can conclude that the Mode Deactivation Therapy (MDT) was effective in improving differentiation of self and psychological well-being of the patients with HSAN-2 through identifying maladjustment core beliefs and replacing them with useful alternatives via the VCR process.