AIM AND BACKGROUND: Multiple sclerosis (MS) is a long-course incurable disease as well as an unknown prognosis causing patients to experience a variety of psychological outcomes. Meanwhile, inability to control the disease-related uncertainty leads to the use of maladaptive coping strategies, causing more psychological distress. This study investigated the effectiveness of intervention focused on the intolerance of uncertainty on psychological distress and quality of life in MS patients. MATERIALS AND METHODS: This research adopted a true experimental design. All phases of the study were conducted online due to the COVID-19 pandemic during 2021 in Tehran. The statistical population of the study was purposefully selected from among MS patients and was randomly assigned to three groups of 20: IU intervention and two control groups (cognitive behavioral therapy (CBT) and treatment as usual (TAU) groups). The study included pre-test, post-test, and follow-up stages. The outcome measures of the study included the Depression Anxiety Stress Scale (DASS-21) as well as Multiple Sclerosis Quality of Life-54 (MSQoL-54). Mixed analysis of variance was used to analyze the data. RESULTS: The results showed that IU intervention compared to CBT, is more effective on psychological distress (depression P = 0.006, anxiety P = 0.01, and stress P = 0.01) and quality of life ( P = 0.001) in MS patients. Nonetheless, IU-focused intervention is more effective than TAU on psychological distress (depression P = 0.0001, anxiety P = 0.0001, stress P = 0.0001) as well as quality of life ( P = 0.0001) in these patients. CONCLUSIONS: IU-based intervention can reduce psychological distress and improve quality of life of MS patients. Accepting uncertainty can reduce the anxiety and stress of MS patients which can increase the quality of life of these patients.