Background: Cladribine is approved for the treatment of highly-active relapsing multiple sclerosis (MS), where it is also effective on disability progression. In the present single-center study, we aim to report on the 8-years clinical follow-up of 27 patients included in phase 2 and 3 clinical trials for cladribine. Methods: We included patients exposed to cladribine (n = 13) or placebo (n = 14) in ONWARD, CLARITY, and ORACLE-MS trials, and followed-up at the same center after trial termination. Outcomes of long-term disease progression were recorded. Results: During 8-year follow-up, patients treated with cladribine presented with reduced risk of EDSS progression (HR = 0.148; 95%CI = 0.031, 0.709; p = 0.017), of reaching EDSS 6.0 (HR = 0.115; 95%CI = 0.015, 0.872; p = 0.036), and of SP conversion (HR = 0.010; 95%CI = 0.001, 0.329; p = 0.010), when compared with placebo. Conclusions: Our exploratory study provides additional evidence that cladribine may be useful to prevent or, at least, mitigate the risk of disability progression after 8 years.