It is well accepted that rehabilitative treatment can be effective in reducing disability and optimizing quality of life (QoL) of people with multiple sclerosis (MS). The aim of this study was to evaluate the effects of a comprehensive outpatient rehabilitative treatment on QoL in patients suffering from MS. We selected 111 patients from a sample of 407 patients who had consecutively entered the MS Center of Catania (which is located in southern Italy) in 1998. Fifty-eight were randomly assigned to the study treatment and 53 to a waiting list (control treatment). Kurtzke's EDSS and quality of Life (QoL)were the primary endpoints. QoL was measured with the generic multi-item SF-36 scales. We also used: the Beck Depression Inventory (BDI) for depression, the Tempelaar Social Experience Check-list (SET) for social activities and the Fatigue Impact Scale (FIS). The study treatment group was treated for 6 consecutive weeks, 6 days a week with a comprehensive rehabilitative outpatient model. The control treatment group was in a waiting list and was trained to self-exercises at home. EDSS remained unchanged in both groups. All health related QoL domains significantly improved in the study treatment (p < 0.001 in physical functioning, role physical, bodily pain, general health, and social functioning; p < 0.05 in vitality, role emotional and mental health). FIS, SET and BDI also improved significantly after the rehabilitative treatment in the study group (p < 0.001). The results of this study confirm the effectiveness of a short comprehensive outpatient model of rehabilitative treatment in people with MS and in particular in their QoL.