Sodium-glucose cotransporter 2 inhibitors such as empagliflozin (EMPA) protect against diabetic kidney disease. PGE2 the main renal product of cyclooxygenase-2, inhibits vasopressin (AVP)-water reabsorption in the collecting duct (CD). We examined if EMPA affects the renal PGE2/EP receptor system and determined if CD responses to EMPA prevent water loss. Four groups of adult male mice were studied after 6 weeks of treatment: control (db/m), db/m+EMPA (10 mg/kg/day in chow), type 2 diabetic (db/db), and db/db+EMPA. Tubules were microdissected for qPCR and CD water transport was measured in response to AVP, with or without PGE2. Hyperglycemia and albuminuria were attenuated by EMPA. Renal mRNA expression for COX, PGE synthase, EP receptors, CD AVP V2 receptors and aquaporin-2 was elevated in db/db mice, but unchanged by EMPA. Urine PGE2 levels increased in db/db but were unchanged by EMPA. AVP-water reabsorption was comparable in db/m and db/m+EMPA, and equally attenuated to 50% by PGE2. In db/db mice, AVP-water reabsorption was reduced by 50% compared to non-diabetic mice, and this reduction was unaffected by EMPA. In db/db mice, AVP-stimulated water transport was more significantly attenuated with PGE2 (62%), compared to non-diabetic mice, but this attenuation was reduced in response to EMPA, to 28%. In summary, expression of renal PGE2/EP receptors is increased in db/db mice, and this expression is unaffected by EMPA. However, in diabetic CD, PGE2 caused a greater attenuation in AVP-stimulated water reabsorption, and this attenuation is reduced by EMPA. This suggests that EMPA attenuates diabetes-induced excess CD water loss.