In the light of known involvement of PGE-2 in mammalian hepatic and muscle regeneration, the possible participation of PGE-2 in wound healing and initiation of caudal regeneration in the lizard, Hemidactylus flaviviridis has been evaluated by assaying the endogenous level in the immediate post-autotomy periods and timed temporal administration. Further, the importance of induced PGE-2 deficiency by the use of COX-2 inhibitor was also evaluated. Overall, the observations suggest no involvement of PGE-2 in the initiation of regeneration, as seen by the similar number of days taken to attain various arbitrary stages of regeneration in both control and experimental lizards, which is confirmed by the down regulation of endogenous PGE-2 level in the immediate post-autotomy periods. Further, the evaluation of PGE-2 as a possible downstream agent of thyroxine, in inducing ependymal growth, by way of administration in hypothyroid lizards also disproved the concept. The role of PGE-2 inferred in lizard tail regeneration is as a cytoprotectant, contributing to the formation of a robust regeneration blastema and augmented tail elongation with higher blastemal cell density, by reduced apoptosis. A schema of possible mechanism of regeneration initiation, in the light of available information, is proposed.