Background and Objectives To determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX). Methods This prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months. Results We included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0–36], median Expanded Disability Status Scale 5 [range 0–8], median follow-up 3.5 years [range 1–5.8], and median number of RTX infusions 5 [range 1–9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0–33.1) were free of any infection and 92.0% (95% CI 87.1–97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75–0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05–1.75, p = 0.01). Discussion In PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.