The effects of some agents which alter the activity or sedimentability of microsomal nucleoside diphosphatase (NDPase) were studied. 2. Trypsin activated NDPase by stimulating endogenous lipid peroxidation. 3. Eighty percent of the NDPase in vesicles was protected from anaerobic proteolytic attack as shown by activity measurements and electrophoresis. 4. Toluene activated NDPase which remained particulate. 5. NDPase and other proteins could then be easily released from microsomes. 6. The nature of the NDPase-membrane interaction is discussed.