Abstract The cis- and trans-alkenols are equally potent general anesthetics but, respectively, lower and raise the gel-to-liquid crystalline phase transition temperature of saturated phosphatidylcholines (Pringle, M.J. and Miller, K.W. (1978) Biochem. Biophys. Res. Commun. 85, 1191–1198). Here we show that although this differential effect is somewhat reduced when a double bond is introduced into the sn-2 position of phosphatidylcholine, it is abolished when the ethanolamine head group is substituted for the choline head group in dimyristoyl lipids at neutral pH. At high pH, however, dimyristoylphosphatidylethanolamine assumes a negative charge, and its phase transition temperature drops to a value close to that for the corresponding phosphatidylcholine. Under these conditions the differential effect of the alkenol isomers is restored; the cis-alkenol lowers, while the trans-alkenol raises, the phase transition temperature of deprotonated dimyristoylphosphatidylethanolamine. Thus, the differential effects of cis- and trans-alkenols on the gel-to-liquid crystalline phase transition are dependent on the physical chemical characteristics of the polar region of the perturbed lipid species, but only weakly on that of the acyl region.