INTRODUCTION Immunosuppressive agents (ISA) have been used in multiple sclerosis (MS) for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS? METHODS We conducted a retrospective multicentre study to investigate the frequency of ISA prescription in 17 Italian MS centres, and to describe the clinical factors related to ISA use. RESULTS Out of 6,447 MS patients, 2,034 (31.6%) were treated with ISA, with Azathioprine being the most frequently used ISA overall. MS patients treated with ISA alone were more frequently affected by the progressive course (both primary and secondary) of the disease (RRR 5.82, 95% CI 4.14-8.16, p<0.0001), had higher EDSS (RRR 3.69, 95% CI 2.61-5.21, p<0.0001), higher assignment age (RRR 1.04, 95% CI 1.03-1.06, p<0.0001) than patients treated with only disease modifying drugs (DMDs). CONCLUSIONS Progressive course, higher EDSS, higher assignment age were the strongest predictors of ISA prescription and use in our population.