1. 1. Haemoglobin-free erythrocyte ghosts were prepared in 40 imosM bicarbonate buffer, pH 7.4, containing 1 mM EDTA (40 imosM/1 mM EDTA). The ghost preparation was highly permeable on preparation but partially resealed on incubation in media containing Ca 2+. 2. 2. A partially purified preparation of phospholipase C from Clostridium welchii caused an increase in observed Mg 2+-ATPase activity, reflecting a change in the permeability of the ghosts to substrate. The phospholipase did not decrease Mg 2+-ATPase even at the highest levels tested. Mg 2+-ATPase activity could therefore be used as a permeability indicator in these experiments. 3. 3. Both (Ca 2+, Mg 2+)-and (Na +, K +, Mg 2+)-ATPase activities of the ghosts were progressively lost as a result of the phospholipid hydrolysis induced by phospholipase C. 4. 4. When a haemolysin in the commercial preparation was destroyed by heat-treatment, deactivation of the (Ca 2+, Mg 2+)-ATPase and (Na +, K +, Mg 2+)-ATPases were still observed but permeability changes were greatly reduced. 5. 5. The products of phospholipase action were not inhibitory to the (Ca 2+, Mg 2+)-ATPase. 6. 6. Lysolecithin brought about a reactivation of the (Ca 2+, Mg 2+)-ATPase which was superimposed upon permeability changes in the preparation. 7. 7. Reactivation of the (Ca 2+, Mg 2+)-ATPase was brought about by a nonlytic mixed lipid preparation without significant effect upon permeability. 8. 8. Human erythrocyte (Ca 2+, Mg 2+)-ATPase therefore appears to be an enzyme which responds to perturbation of the lipid environment in the membrane and is a “lipid-dependent” enzyme.