Background: Psychological distress and psychiatric co-morbidity are common in multiple sclerosis (MS) and is often associated with neurological disability as well as reduced quality of life. Objectives:This study aimed to investigate psychological distress and the possible association with quality of life as well as neurological disability in MS patients within the first 3 years after diagnosis. Methods: Psychological distress was measured using a standardized questionnaire (Symptom-Check-List-90-R; SCL-90-R) in 31 relapsing-remitting MS patients and 24 sex- and age-matched healthy controls. Results: Psychological distress was significantly more pronounced in MS patients when compared to healthy controls. Interpersonal sensitivity and psychoticism were positively associated with neurological disability (Expanded Disability Status Scale [EDSS]). A high EDSS group (median split EDSS; 1.5) expressed significantly more psychological distress when compared to the low EDSS group and healthy controls. MS patients with minimal to no neurological disability (low EDSS group) also expressed significantly more emotional distress when compared to healthy controls. MS-related quality of life was positively associated with neurological disability as well as SCL-90-R scores. After adjusting for neurological disability, psychological distress was still significantly associated with quality of life. Conclusions: Early stage MS patients significantly differ in their psychological distress when compared to healthy controls. Psychological distress in these patients is associated with neurological disability, but it is also present in patients with minimal to no neurological disability. Psychological distress was identified as an independent predictor for MS-related quality of life.