This large cohort study from the US Premier Healthcare Database evaluated the risk and predictors of anaphylaxis in association with intravenous immunoglobulin (IVIg) therapy in the inpatient and outpatient setting. Data were collected retrospectively (01/2009-12/2018) from 24,919 patients administered IgPro10 IVIg, median age 54 years. Immunoglobulins of interest were IgPro10 and other IVIg given before or after IgPro10. Moderate and severe anaphylaxis was identified from same-day parenteral epinephrine and IVIg use and reviews of patient record summaries. Predictors for first anaphylactic reactions associated with IVIg administration were derived from adjusted incidence rate ratios (IRR) using Poisson regression. Moderate anaphylaxis in IVIg use was rare, severe anaphylaxis very rare based on a total of 124 moderate and four non-fatal severe first anaphylactic events, incidence rate of 7.11 and 0.23/10,000 IVIg administrations respectively. Age under 18 was an independent predictor of moderate or severe anaphylactic events, adjusted IRR 2.94 (0.95-CI, 1.91-4.52) compared with those 18 years and older. First IVIg administration was a strong predictor of anaphylaxis. The IRR in those with a subsequent IVIg administration in the preceding 42 days, decreased to 0.27 (0.17-0.42) and in those effectively IVIg-naïve (no IVIg for > 42 days) to 0.76 (0.44-1.32) compared with first IVIg use. The key conclusions from this study are that the risk of anaphylaxis has progressively reduced over the last decade, from 14.87/10,000 in 2009-2010 to 4.39/10,000 IVIg administrations in 2017-2018 and is rare overall, and that the risk of anaphylaxis is increased in those aged under 18.