Guest exchange in an M4L6 supramolecular host has been evaluated to determine whether host rupture is required for guest ingress and egress. Two mechanistic models were evaluated: one requiring partial dissociation of the host structure to create a portal for guest passage and one necessitating deformation of the host structure to create a dilated aperture for guest passage without host rupture. Three related lines of inquiry support the nondissociative guest exchange mechanism. (a) Equally facile guest exchange is observed in labile ([Ga4L6](12-)) and inert ([Ti4L6](8-) and [Ge4L6](8-)) hosts. (b) Molecular mechanics calculations demonstrate that the structural deformations required for enlargement of an M4L6 aperture in a nonrupture or nondissociative guest exchange mechanism are plausible. (c) As predicted by the calculations, COCP2*+, a sterically demanding guest, significantly inhibits guest exchange. These results bring new insight to the application of the M4L6 supramolecular host for encapsulated reaction chemistry for which there are now several examples.