Drug-dependent IgG antibodies (DDAb) induced by sulfamethoxazole (SMX) and sulfisoxazole (SIX) were identified by flow cytometry in 15 patients who developed thrombocytopenia while taking one of these medications. Fourteen of the 15 DDAb were specific solely for the glycoprotein (GP)IIb/IIIa complex, and 13 of these reacted wholly or in part with epitopes present only on the intact GPIIb/IIIa heterodimer. None of 12 SMX-induced DDAb cross-reacted with SIX, but one of three SIX-induced antibodies reacted with SMX. Each of 10 SMX-induced DDAb tested reacted with the N1-acetyl metabolite of SMX, but only one reacted fully with the N4-acetyl derivative. Detection of the SMX- and SIX-dependent antibodies was facilitated by using bovine serum albumin (BSA) to achieve suspension of these weakly soluble drugs in an aqueous medium. Our findings indicate that DDAb induced by SMX and SIX, in contrast to those induced by quinidine and quinine, are mainly specific for GPIIb/IIIa and react preferentially with calcium-dependent epitopes present only on the intact GPIIb/IIIa heterodimer.