Tyrosinamidomethyl dihydrohaloisoxazoles (THX) irreversibly inhibit isolated epidermal transglutaminases and ionophore-induced cell envelope formation in malignant human keratinocytes. In cultured human foreskin keratinocytes cultured in 10(-5) M THX for 5 days, soluble and particulate transglutaminases were inhibited by 90% and 44-51%, respectively. Spontaneous cell envelope formation was inhibited up to 54%. When THX-treated keratinocytes were simultaneously incubated with 10(-5) M retinoic acid (RA), there was enhanced inhibition of cell envelope formation compared to either agent alone. The inhibitors were equally effective in keratinocytes incubated with fetal calf serum or delipidized serum. After THX was applied to normal human thoracic skin in vivo for 9 d, the soluble and particulate transglutaminases isolated from suction blister epidermis were inhibited 30% and 40%, respectively. THX may be effective in inhibiting both soluble and particulate transglutaminase activity in disorders with increased transglutaminase activity.