Abstract Diphenhydramine, chlorpromazine, and promethazine do not inhibit the initial adjustment of isolated liver mitochondria to hypotonie medium. Chlorpromazine and promethazine in optimum concentrations do inhibit glutathione- or ascorbate-induced swelling-lysis, late isotonic swelling, and a late or second phase of hypotonie swelling. In isotonic medium they do not inhibit electron transport-dependent swelling except in very much greater concentrations, and then only partially. Diphenhydramine does not inhibit glutathione- or ascorbate-induced swelling-lysis, late isotonic swelling, or electron transport-dependent swelling in isotonic medium. In most cases it does inhibit late swelling of mitochondria in hypotonie media. Late swelling of fresh mitochondria in very hypotonie medium may have some relation to electron transport, since it is inhibited by 2, 4-dinitrophenol and most electron transport inhibitors, but late swelling under other circumstances is not. The late swelling of fresh mitochondria in very hypotonic medium, like the late swelling in isotonic medium and most other circumstances, is inhibited by the antioxidant butylated hydroxyanisole, so that lipid peroxidation may be responsible for the changes. With DPHA there is clear indication of a membrane-stabilizing effect independent of electron transport inhibition, uncoupling, or antioxidant activity. With the phenothiazines, the powerful antioxidant action makes it more difficult to determine whether the stabilizing action is direct like that of DPHA or is the result of preventing peroxidation, but they do inhibit swelling in some circumstances when BHA is inactive. The aging of isolated mitochondria results in some membrane change which greatly slows their initial adjustment to hypotonic medium.