A detailed kinetic study of the endo-selective epoxide-opening cascade reaction of a diepoxy alcohol in neutral water was undertaken using H-1 NMR spectroscopy. The observation of monoepoxide intermediates resulting from initial endo and exo cyclization indicated that the cascade proceeds via a stepwise mechanism rather than through a concerted one. Independent synthesis and cyclization of these monoepoxide intermediates demonstrated that they are chemically and kinetically competent intermediates in the cascade. Analysis of each step of the reaction revealed H H that both the rate and regioselectivity of cyclization improve as the cascade reaction proceeds. In the second step, cyclization of an epoxy alcohol substrate templated by a fused diad of two tetrahydropyran rings proceeds with exceptionally high regioselectivity (endo:exo = 19:1), the highest we have measured in the opening of a simple trans-disubstituted epoxide. The origins of these observations are discussed.