This study investigates the relationship between rituximab treatment, hypogammaglobulinemia, and infection risk in patients with multiple sclerosis (pwMS). The objectives were to estimate the extent to which rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors. A retrospective cohort study was conducted using data from Kaiser Permanente Southern California, including 2,482 pwMS treated with rituximab from 2008 to 2020. Cumulative rituximab dose was categorized as ≤2 g, >2–4 g, or >4 g. Serious infections were defined as those requiring hospitalization, and recurrent outpatient infections were defined as seeking care for ≥3 infections within 12 months. Higher cumulative rituximab doses were associated with lower IgG levels, and both higher cumulative doses and lower IgG levels independently increased the risk of serious and outpatient infections. Hypogammaglobulinemia explained at most 17.9% of the increased risk of serious infections associated with higher cumulative rituximab exposure. Advanced physical disability was a significant independent risk factor for serious and outpatient infections. Other modifiable risk factors included obesity, COPD, and diabetes. The findings suggest that higher cumulative rituximab doses increase infection risk primarily through mechanisms other than hypogammaglobulinemia, and that advanced disability is a key driver of infection risk in pwMS. The study highlights the need to optimize dosing regimens and consider comorbidities when managing infection risk in pwMS.This study investigates the relationship between rituximab treatment, hypogammaglobulinemia, and infection risk in patients with multiple sclerosis (pwMS). The objectives were to estimate the extent to which rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors. A retrospective cohort study was conducted using data from Kaiser Permanente Southern California, including 2,482 pwMS treated with rituximab from 2008 to 2020. Cumulative rituximab dose was categorized as ≤2 g, >2–4 g, or >4 g. Serious infections were defined as those requiring hospitalization, and recurrent outpatient infections were defined as seeking care for ≥3 infections within 12 months. Higher cumulative rituximab doses were associated with lower IgG levels, and both higher cumulative doses and lower IgG levels independently increased the risk of serious and outpatient infections. Hypogammaglobulinemia explained at most 17.9% of the increased risk of serious infections associated with higher cumulative rituximab exposure. Advanced physical disability was a significant independent risk factor for serious and outpatient infections. Other modifiable risk factors included obesity, COPD, and diabetes. The findings suggest that higher cumulative rituximab doses increase infection risk primarily through mechanisms other than hypogammaglobulinemia, and that advanced disability is a key driver of infection risk in pwMS. The study highlights the need to optimize dosing regimens and consider comorbidities when managing infection risk in pwMS.