The calcium-dependent ATPase from sarcoplasmic reticulum of rabbit has been purified and reconstituted in dispersions containing pure phosphatidylcholines. Each phosphatidylcholine (PC) had palmitate (16:0) at the sn-1 position of glycerol and stearate (18:0), oleate (18:1), linoleate (18:2), arachidonate (20:4), or docosahexaenoate (22:6) at the sn-2 position. The activities and activation energies of the enzyme indicated that the best enzyme function occurred when 16:0–18:1 PC or 16:0–18:2 PC was the lipid in which the ATPase was embedded. Circular dichroism measurements made as a function of temperature suggested that the protein in 16:0–18:0 and 16:0–18:1 PC behaved most like sarcoplasmic reticulum or purified ATPase. The results suggest that there may be an optimal lipid environment for the ATPase which is provided by 16:0–18:1 PC and 16:0–18:2 PC, the two most common lipids of the sarcoplasmic reticulum.Key words: lipid–protein interactions, adaptation, mixed acid lipids.