The possible involvement of mast cell proteases in the cutaneous inflammation of herpes zoster was studied histochemically in ten patients. Mast cell tryptase and chymase bioactivities were demonstrated enzyme-histochemically. The localization of protease inhibitors as well as tryptase and chymase proteins in mast cells was established using a sequential double-staining method which first demonstrated bioactive tryptase or chymase, followed by immunohistochemical identification of these antigens. Biopsies were taken from involved vesicular and erythematous skin, as well as from normal healthy-looking skin. Tryptase-bioactive mast cells were significantly lower in number in the upper, but not in the deeper dermis of vesicular skin (68±37 cells/mmmean±SD) when compared with either healthy-looking (97±38) or erythematous skin (105±36) (t-test, P<0·005). In contrast, chymase-bioactive mast cells were significantly reduced in number both in erythematous skin (44±20, P<0·02) and even more so in vesicular skin (26±20, P<0·0005) when compared with healthy-looking skin (64±27). The percentage of α1-antitrypsin-immunoreactive and α1-antichymotrypsin-immunoreactive mast cells in the upper dermis increased steadily from the values in healthy-looking skin (37·9±18·8 and 82·5±21·6 per cent) to those in erythematous (64·4±16·4 and 93·5±7·9 per cent) and vesicular skin (75·2±10·2 and 96·4±4 per cent). A novel finding was that cells showing tryptase immunoreactivity but no enzyme activity were found in two out of nine erythematous skin specimens and in four out of seven vesicular specimens. In healthy-looking skin, all cells with chymase immunoreactivity also displayed chymase bioactivity, but only 53·2±24·25 per cent of these mast cells in erythematous lesions and 44·4±15·9 per cent in vesicular lesions showed chymase bioactivity, suggesting inactivation of chymase by protease inhibitors. These results show prominent alterations in mast cell proteinases and protease inhibitors, indicating that these enzymes participate in the cutaneous inflammation due to herpes zoster.