Glucose-6-phosphate dehydrogenase (G6PDH) from hepatopancreas of the land snail, Otala lactea, shows distinct changes in properties between active and estivating (dormant) states, providing the first evidence of pentose phosphate cycle regulation during hypometabolism. Compared with active snails, G6PDH V_max increased by 50%, K_m for glucose-6-phosphate decreased by 50%, K_a Mg·citrate decreased by 35%, and activation energy (from Arrhenius plots) decreased by 35% during estivation. DEAE–Sephadex chromatography separated two peaks of activity and in vitro incubations stimulating protein kinases or phosphatases showed that peak I (low phosphate) G6PDH was higher in active snails (57% of activity) whereas peak II (high phosphate) G6PDH dominated during estivation (71% of total). Kinetic properties of peaks I and II forms mirrored the enzyme from active and estivated states, respectively. Peak II G6PDH also showed reduced sensitivity to urea inhibition of activity and greater stability to thermolysin protease treatment. The interconversion of G6PDH between active and estivating forms was linked to protein kinase G and protein phosphatase 1. Estivation-induced phosphorylation of G6PDH may enhance relative carbon flow through the pentose phosphate cycle, compared with glycolysis, to help maintain NADPH production for use in antioxidant defense.