At normal extracellular 40Ca concentration (1.0--1.5 mM), D-glucose initially reduces and subsequently increases 45Ca efflux from prelabeled rat pancreatic islets, whether in the absence or presence of 20 mM Ca-EGTA. Thus, the initial fall cannot be attributed to a reuptake of effluent 45Ca. Both the fall and rise in effluent 45Ca represent sustained and rapidly reversible phenomena partially masked by one another. The dose-action relationship for the initial fall in 45Ca efflux (Km = 4.2 mM) differs vastly from that characterizing the secondary rise in 45Ca efflux (Km = 9.1 mM). Mannoheptulose, iodoacetate, and low temperature inhibit both the early fall and secondary rise in effluent radioactivity normally evoked by glucose. D-Glucose (8.3 mM) and D-glyceraldehyde (10 mM) exert comparable effects on 45Ca efflux. The initial fall and later increase in 45Ca efflux evoked by glucose, although dependent on the integrity of glucose metabolism, correspond to two distinct processes in the rapid regulation of Ca handling by the islet cells.