This study explored changes in quality of life (QOL) and psychosocial variables in a large cohort of people with multiple sclerosis (MS). A total of 1287 Australians with MS were administered self-report questionnaires at baseline and 24 months later to examine the impact of disease severity and duration, perceived stress, self-efficacy, depression, and social support on QOL and self-care. Over the 2-year survey period, MS remained stable for 70% of respondents. Disease severity correlated with social support at baseline but not at 24 months, when the only significant correlation with disease severity was that of the World Health Organization Quality of Life-100 instrument (WHOQOL-100) domain of Level of Independence. Although QOL improved across the WHOQOL-100 domains Physical, Psychological, Level of Independence, Social Relationships, and Environment, decreases were found in the WHOQOL-100 facet overall QOL and well-being as well as self-efficacy over the same time period. Hierarchical multiple regression was used to assess the utility of four control measures. MS disease severity and MS disease duration were entered at Step 1, explaining 16.1% of the variance in QOL. After entry of perceived stress, self-efficacy, social support, and the Depression, Anxiety and Stress Scale-21 (DASS-21) at Step 2, the total variance explained by the model as a whole was 55.8% (F6,1028 = 216.495, P < .001). Thus, even in the presence of stable disease and improvement in some WHOQOL-100 domains, overall QOL and self-efficacy had decreased at 2 years after the collection of baseline data. Loss of self-efficacy, increased stress, and depression are key factors in reduced QOL in people with MS.