Rituximab, a B-cell-depleting therapy used in multiple sclerosis (pwMS), is associated with increased infection risk and hypogammaglobulinemia. This study analyzed 2,482 pwMS treated with rituximab from 2008 to 2020, finding that higher cumulative rituximab doses were linked to lower IgG levels and increased infection risk. Hypogammaglobulinemia explained only 17.9% of the increased risk of serious infections but not outpatient infections. Other modifiable risk factors included advanced disability, COPD, and obesity. The study highlights that even with normal IgG levels, higher rituximab doses increase infection risk. Clinicians should use minimally effective doses and consider comorbidities to reduce infection risks. The findings suggest that B-cell-depleting therapies may be less beneficial in patients with advanced disability, and further research is needed to determine the lowest effective dose. The study underscores the importance of monitoring IgG levels and managing comorbidities in pwMS.Rituximab, a B-cell-depleting therapy used in multiple sclerosis (pwMS), is associated with increased infection risk and hypogammaglobulinemia. This study analyzed 2,482 pwMS treated with rituximab from 2008 to 2020, finding that higher cumulative rituximab doses were linked to lower IgG levels and increased infection risk. Hypogammaglobulinemia explained only 17.9% of the increased risk of serious infections but not outpatient infections. Other modifiable risk factors included advanced disability, COPD, and obesity. The study highlights that even with normal IgG levels, higher rituximab doses increase infection risk. Clinicians should use minimally effective doses and consider comorbidities to reduce infection risks. The findings suggest that B-cell-depleting therapies may be less beneficial in patients with advanced disability, and further research is needed to determine the lowest effective dose. The study underscores the importance of monitoring IgG levels and managing comorbidities in pwMS.