The aim of this study is to investigate the long-term effects of the initial spinal cord (SC) involvement in MS patients. In this retrospective, single-center study, 824 patients with definite MS were screened. A total of 348 patients were excluded for ambiguous documentation of the initial relapse, pediatric onset, diagnosis of primary progressive disease, irregular assessments or visits causing doubt on the onset of progression time, and clinical follow-up duration less than 12 months. Eventually, 476 MS patients were included. Data regarding the demographics, initial symptoms, the degree of recovery from the initial relapse, neuroimaging, cerebrospinal fluid analysis, long-term disability, and progression were collected from the medical registry. The mean duration of follow-up was 7.49 ± 5.30 years. The percentage of patients entering the progressive disease course was 23.3 in the whole group. A total of 157 patients (33.0%) had SC involvement during the first clinical relapse. These patients were significantly older at disease onset (31.69 ± 10.18 vs. 29.55 ± 9.49; p = 0.028), had higher rates of progression (32.5 vs. 18.8%; p = 0.001), and had higher disability scores in long-term follow-up (3.41 ± 2.19 vs. 2.62 ± 1.81; p < 0.001). Mean age at the transition of progressive phase was 41.4 ± 11.2 years. The degree of recovery from the initial relapse significantly affected the long-term disability. The poor recovery from the initial relapse was associated with older onset age and higher EDSS scores. Being older than 40 years during MS onset and poor recovery from the initial relapse exerted an increased risk for progression. The initial SC involvement was related to a more severe relapse with less chance of complete recovery and higher risk for progression. Confirmation of risk factors in different MS cohorts would increase our understanding of the complex disease mechanisms.