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Tools to identify patients with IgGSD who benefit from immunoglobulin G replacement therapy (IgGRT) are lacking. This crossover study evaluated the number of antibiotic-demanding infections on and after up to 18 mo off IgGRT in 28 patients with IgGSD. Pneumococcal antibodies against 21 serotypes were assessed using a multiplex assay. After 12 mo on IgGRT, the frequency of infections was reduced during the following 6 mo compared with the last 6 mo without IgGRT, indicating a delayed therapeutic effect. Low levels of pneumococcal serotype-specific antibodies and lower IgG2 levels were associated with the need to restart IgGRT. In conclusion, IgGRT effectively reduces bacterial infections in IgGSD, but the benefits may take at least a year to manifest. 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