This study assessed the real-world effectiveness of immunoglobulin replacement therapy (IgRT) for treatment of hypogammaglobulinemia and infections in patients with multiple myeloma (MM). A retrospective study was conducted on adult patients diagnosed with MM on or after 1 January 2010 using the Mass General Brigham Research Patient Data Registry. Infections were compared before and after IgRT initiation. Generalized estimating equation logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). In patients with accessible serum protein electrophoresis (SPEP) test results, a Natural Language Processing program supported the extraction of immunoglobulin G (IgG) data. The IgG assessments and incidence of hypogammaglobulinemia (defined as IgG level <500 mg/dL) were compared before and after IgRT initiation. The results were reported using descriptive statistics. A total of 6062 patients with MM were identified (56.2% male; median age, 65.0 years). Of the 6062 patients, 471 (7.8%) received ≥1 IgRT administrations. At 3 months, significantly lower odds of infections (OR, 0.71; 95% CI, 0.56-0.89; P = .0004) were observed after IgRT initiation than before IgRT. Among patients with accessible SPEP results (n = 3405), 3231 (94.9%) underwent ≥1 IgG test with a median of 18.0 (interquartile range, 7.0-40.0) IgG tests per patient. Hypogammaglobulinemia was experienced by 2075 of the 3231 patients (64.2%) who had ≥1 IgG test. Significantly fewer patients had hypogammaglobulinemia after IgRT initiation. In conclusion, IgRT use was associated with significant reductions in hypogammaglobulinemia and infections. Although IgRT is currently used for MM treatment, there is potential to optimize its dosing and treatment duration to reduce the morbidity and mortality associated with infections.