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Background & Aims: Individuals who mount a significant serum immunoglobulin (Ig)G response to toxin A are protected against recurrent Clostridium difficile–associated disease (CDAD). We investigated whether humoral immune deficiencies and/or specific IgG subclass responses are associated with recurrent CDAD. Methods: We compared the clinical characteristics and humoral immune responses of 13 patients with recurrent CDAD with 13 matched controls with a single CDAD episode. We measured the serum IgG titers to tetanus and diphtheria toxoids, as well as total and toxin A– and toxin B–specific serum IgG, IgA, and IgG subclass concentrations. Results: There were no differences between the single and recurrent CDAD subjects in terms of age, sex, ethnicity, or other potential confounding variables. The total duration of diarrhea in patients with recurrent CDAD was greater (median, 62 vs 17 days; P = .005). IgG titers to tetanus and diphtheria toxoids, total IgG, and IgG subclass levels were similar in both groups. The total IgA was somewhat lower in those with recurrent CDAD (204 vs 254 mg/dL; P = .05). IgA, IgG, IgG1, and IgG4 anti–toxin A and anti–toxin B levels were similar in both groups. However, IgG2 and IgG3 anti–toxin A levels were significantly lower in the recurrent group (P = .01 and .001, respectively). Conclusions: Subjects with recurrent CDAD did not show evidence of widespread humoral immune deficiency or of IgG subclass deficiency. Their low serum IgG anti–toxin A concentrations reflected selectively reduced IgG2 and IgG3 subclass responses. Measurement of specific IgG2/3 anti–toxin A may be useful in selecting patients for treatment with agents to prevent recurrent CDAD. [Copyright &y& Elsevier]