The possible acantholytic property of captopril and thiopronine has been investigated using in vitro tissue cultures. Normal human breast skin explants have been cultured in Hanks’ balanced salt solution containing 40% normal inactivated human serum with the addition of L-cysteine, or reduced glutathione (GSH), or captopril, or thiopronine, at four different concentrations (1, 5, 10, 15 mM). Patterns of diffuse, mainly suprabasal acantholysis, with formation of bullae, were observed in the skin explants cultured with captopril or thiopronine at a 15-mM concentration after 5 days of culture; intraepidermal splits were present also at a 10-mM concentration. Focal acantholysis was seen in specimens cultured with L-cysteine or GSH at a 15-mM concentration. No lesions occurred in the samples treated with lower concentrations of the above substances, nor in controls. The results show a biochemical acantholytic potential of both captopril and thiopronine, resembling that of penicillamine in similar experimental conditions, and consonant with clinical observations of pemphigus induced by drugs containing thiol groups in their molecule (SH drugs