BACKGROUND: Concerns have arisen regarding the potential impact of the coronavirus disease 2019 (COVID-19) pandemic on increasing the incidence and relapse rates of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) due to vaccination against severe acute respiratory syndrome coronavirus-2. However, confirmation of this relationship is still lacking. OBJECTIVE: The primary objective of this study was to compare relapse rates among patients with MS and NMOSD between the pre-pandemic and pandemic eras. The secondary objective was to determine the incidence of newly diagnosed cases of MS and NMOSD and analyze the relationship between COVID-19/vaccination and relapse. METHODS: We divided the study period into two phases: the pre-pandemic era (January 1, 2017, to December 31, 2019) and the pandemic era (January 1, 2020, to December 31, 2022). Relapse events were compared between the two periods. Multivariate time-to-event techniques were used to assess relapse rates between both periods using the Anderson-Gill (AG), Prentice, Williams, and Peterson (PWP), total time (TT) and gap time (GT), and Cox frailty models. RESULTS: A total of 697 data contributions from 405 patients with MS and NMOSD were evaluated and categorized into two groups: the pre-pandemic group (n = 328) and the pandemic group (n = 369). A total of 1720.21 person-years were recorded, with 794.38 and 925.83 person-years before and during the pandemic, respectively. The results showed that the relapse rates of MS and NMOSD did not differ significantly between the pre-pandemic and pandemic periods (p = 0.96). The relapse rate did not change significantly between the two periods after adjusting for rituximab use and disease duration, as demonstrated by the different statistical models for multiple events (AG model), event-specific inter-individual analyses (PWP-TT and PWP-GT), and intra-individual analyses (Cox frailty model). CONCLUSION: These results suggest that there is insufficient evidence to establish a link between COVID-19 or COVID-19 vaccination and a higher frequency of relapse in patients with MS and NMOSD.