Abstract Background European data indicate that systemic sclerosis (SSc)-related death rates are increasing, thus raising concerns about SSc’s optimal management. Herein, we describe current treatment modalities and drug survival in a real-life SSc cohort. Methods Details on immunosuppressive/antiproliferative (methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, tocilizumab) and vasoactive agent [(endothelin receptor antagonists (ERAs), sildenafil, iloprost, and calcium channel blockers (CCB)] administration during the disease course (11.8 ± 8.4 years, mean + SD) of 497 consecutive patients examined between 2016 and 2018 were retrospectively recorded. Drug survival was assessed by Kaplan–Meier analysis. Results Methotrexate was the most frequently administered immunosuppressive/antiproliferative agent (53% of patients), followed by cyclophosphamide (26%), mycophenolate (12%), and azathioprine (11%). Regarding vasoactive agents, CCB had been ever administered in 68%, ERAs in 38%, iloprost in 7%, and sildenafil in 7% of patients; 23% of patients with pulmonary fibrosis had never received immunosuppressive/antiproliferative agents, 33% of those with digital ulcers had never received ERAs, iloprost, or sildenafil, whereas 19% of all patients had never received either immunosuppressive/antiproliferative or other than CCB vasoactive agents. Survival rates of methotrexate, cyclophosphamide, and mycophenolate differed significantly, being 84/75%, 59/43%, and 74/63% at 12/24 months, respectively, with inefficacy being the most frequent discontinuation cause. Conversely, CCB, ERAs, and sildenafil had high and comparable retention rates of 97/91%, 88/86%, and 80/80%, respectively. Conclusions Existing therapeutic limitations indicate that more evidence-based treatment is warranted for successful management of SSc. Vasculopathy seems to be managed more rigorously, but the low retention rates of immunosuppressive/antiproliferative drugs suggest that effective and targeted disease-modifying agents are warranted.