The existing knowledge about the health-related quality of life (HRQoL) and its relationship to cognitive and/or emotional functioning in multiple sclerosis (MS) is scarce. We assessed differences between subgroups of MS outpatients (n = 209) on one HRQoL instrument: a version of the Functional Assessment of Multiple Sclerosis quality of life instrument; on two cognitive functioning tests: the Mini-Mental State Examination and the clock drawing test; and on two emotional functioning tests: the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety. Three disease-related characteristics were assessed: physical disability, duration of the illness, and clinical course. The results showed that each of these has an effect on at least one dimension of HRQoL and on one mental functioning test. Thus, the more severe, the more progressive, and the longer the illness duration, the lower the HRQoL. Likewise, cognitive mean scores decreased and emotional mean scores increased with greater illness severity and progressive the MS. Furthermore, we also found significant correlations between cognitive and emotional functioning tests and HRQoL dimensions. Thus, the worse cognitive functioning and the higher depressive and anxiety symptoms score the lower the HRQoL.