Background: Natalizumab, an efficacious treatment for relapsing forms of multiple sclerosis, has an approved dosing of 300 mg infused intravenously over 1 h every 4 wk, with patient monitoring for infusion-related reactions (IRRs) recommended during infusion and for 1 h afterwards. Recently, low rates of natalizumab IRRs during postinfusion monitoring have been reported. Detailed data on the timing and severity of natalizumab IRRs could help further inform on infusion risks. Objectives: To evaluate the frequency and severity of IRRs occurring around the time of infusion including adverse events (AEs), AEs of hypersensitivity, and acute-onset serious AEs (SAEs) and SAEs of hypersensitivity requiring immediate medical intervention, in association with natalizumab exposure duration. Methods: The analysis population included patients from 14 clinical studies of natalizumab. Patients with natalizumab exposure prior to study enrollment were excluded. All SAEs reported during infusion or postinfusion monitoring on the day of infusion were included. Incidence and severity of SAEs and SAEs of hypersensitivity were analyzed by natalizumab exposure duration and by infusion/postinfusion time. Results: The at-risk patient population included 3028 patients who received ?1 dose of natalizumab. During the first 6 mo of treatment, 260 (8.6%) and 14 (0.5%) of 3028 patients reported 554 AEs and 14 SAEs, respectively, during infusion, and 134 (4.4%) and 4 (0.13%), patients reported 212 AEs and 4 SAEs, respectively, during the1st h postinfusion, with fewer AEs and SAEs reported >2 h postinfusion. From >6 mo to ?12 mo of treatment, 83 (3.9%) and 4 (0.19%) of 2116 patients reported 176 AEs and 4 SAEs, respectively, during infusion, and 51 (2.4%) patients reported 74 AEs and no SAEs during the 1st h postinfusion, with fewer events reported after 2 h. The numbers of patients who experienced AEs and SAEs declined over subsequent 6 mo exposure intervals. Similar trends were observed for AEs and SAEs of hypersensitivity. There were no reports of SAEs in patients with >36 mo exposure. Conclusions: The incidence of SAEs and SAEs of hypersensitivity decreased with natalizumab exposure duration and postinfusion time. Most serious events were reported within the first 612 months of treatment and during the infusion period. These results may help inform healthcare providers on when the risk of natalizumab IRRs requiring intervention during and after infusion is greatest.