In our study, we examined whether health-related quality of life (HRQoL) could predict changes in disability, depression, and fatigue in patients with multiple sclerosis (MS) over a 3-year follow-up period. A group of 109 consecutive MS patients (McDonald's criteria) referring to the Institute of Neurology, Belgrade were enrolled in the study. At two time points during the study (baseline, and after a 3-year period) an HRQoL (measured by MSQoL-54), EDSS, Hamilton Rating Scale for Depression (HDRS) and Fatigue Severity Scale (FSS) were assessed. At the end of a 3-year follow-up, 12 out of 109 patients (11%) had dropped out. Multiple linear regression analysis showed that Physical Health scale of MSQoL-54 is significant independent predictor of change in EDSS after 3 years (p = 0.035). Mental health composite score of MSQoL-54 was predictor of change in HDRS score (p = 0.049). In separate regression analysis, only social function was independent predictor of the development of depression (p = 0.041). None of the HRQoL domains had predictive effect on the change of FSS. Our study suggests that baseline HRQoL scores, measured by MSQoL-54, could be applied as a prognostic marker for progression of both, disability, and severity of depressive symptoms in MS.