Murine OKT3 monoclonal antibodies function as an immunosuppressant drug for organ transplant recipients. A contraindication to retreatment may develop, however, because a high proportion of OKT3-treated patients form anti-OKT3 antibodies. Previous data have shown that only antiidiotypic IgG antibodies can negate the beneficial effect of the drug. Eighty-two OKT3-treated transplanted patients were tested by ELISA for IgG, IgK and IgA anti-OKT3 antibodies and compared with 200 controls. The anti-OKT3 antibody-positive sera were screened additionally by flow cytometry for the presence of antiidiotypic activity by measuring Ortho OKT3-FITC activity on a CD3-positive cell line, Jurkat, before and after incubation with serial dilutions of patient and control sera. Forty-four of 82 patients developed antibodies to OKT3, 20 manifested IgG, 20 produced both IgG and IgA, and 4 IgA only. We never detected IgM anti-OKT3. Of the 44 anti-OKT3-positive patient sera, 25 showed antiidiotypic specificity. Two IgG/IgA anti-OKT3-positive patient sera were IgG-depleted by Protein G. Both continued to exhibit antiidiotypic IgA activity. IgA anti-OKT3 was associated with low serum OKT3 levels and lack of ability of OKT3 to lower total CD3 cell numbers to therapeutic levels. This is the first report of IgA anti-OKT3 antibody in transplant recipients. Isotype IgA anti-OKT3 was observed in 54% of the patients whose sera tested positive for anti-OM by ELISA. The IgG/ IgA anti-OKT3-positive patient sera tested continued to exhibit antiidiotypic OKT3 reactivity when depleted of IgG. We urge that OKT3-treated patients be monitored routinely for IgA anti-OKT3 antibodies to avoid the expense and potential complications of retreatment with this drug in sensitized patients.