Optimizing quality of life (QOL) and self-management in people with multiple sclerosis (MS) is increasingly seen as a worthwhile goal. This study aimed to investigate factors that affect QOL in MS. A large national sample of Australians with MS (n = 1848) generated from the Australian Multiple Sclerosis Longitudinal Study completed a survey addressing disease duration and severity, self-efficacy, depression, perceived stress, social support, QOL, and self-management. We tested a model of self-help in which antecedent variables are influenced by mediating variables, which in turn affects outcome variables. In the current study, the antecedent variables were disease duration and disease severity; the mediating variables were self-efficacy, depression, perceived stress, and social support; and the outcome variables were QOL and self-management. We also tested the hypothesis that disease severity, depression, and perceived stress would correlate inversely with QOL and potential for self-management, whereas self-efficacy and perceived level of social support would correlate positively with QOL and potential for self-management. The results indicated that the antecedent variables did not correlate with the mediating variables, with one exception: a negative correlation was found between disease severity and social support. No correlations were found between social support and QOL or self-management. However, significant correlations were found between depression, self-efficacy, stress, and social support and QOL. No correlations were found between either the antecedent or the mediating variables and self-management. The results confirm previous findings of statistically significant correlations between psychosocial factors and QOL.