We compared two methods of calcium gluconate infusion to maintain plasma ionized calcium ([Ca ]) during therapeutic plasma exchange (TPE) performed using the Spectra Optia Apheresis System. Method A, our legacy method, consisted of adding 5 mL of 10% calcium gluconate to each 500 mL bottle of 5% albumin replacement fluid. Method B used an accessory IV infusion of calcium gluconate (2 g in 50 mL of 0.9% NaCl starting at 25 mL/h). Plasma [Ca ] was measured at 20-minute intervals, and symptoms of hypocalcemia were recorded during TPE. Baseline [Ca ] was the same (P = 0.616), as was total acid citrate dextrose Formula A used (P = 0.865), with either method. TPE with method A used 2.62 ± 0.52 g of calcium gluconate vs 1.13 ± 0.27 g with method B (P < 0.001). [Ca2+] remained stable with method A (P = 0.251), but fell on average by 5% with method B (P < 0.05). Hypocalcemic symptoms were reported in 0 of 23 TPE with method A and 2 of 24 TPE with method B. We conclude that both methods A and B prevent a symptomatic fall in plasma [Ca ] during TPE. Method B requires significantly less calcium gluconate than does method A.