Acid whey from Greek-style yogurt (GSY) is characterized by a high mineral content and low pH, which cause challenges for both its utilization as an ingredient or further processing. For example, the high concentration of calcium phosphate in GSY acid whey can lead to fouling during membrane processing, including reverse osmosis (RO) for concentration or ultrafiltration (UF) for fractionation. In this work, we sought to improve the filterability of GSY acid whey by developing an optimized pretreatment before membrane filtration. The pretreatment approach was to precipitate Ca by addition of phosphate salts. GSY acid whey (average pH = 4.4) was sourced from a NY State dairy. The effects of pH (6 to 10), calcium-to-phosphorus (Ca/P) ratio (0.3 to 1.3), temperature (40 to 70°C), and holding time (10 to 60 min) on Ca removal from acid whey were evaluated using response surface methodology. A central composite orthogonal design was employed, with 30 experiments per replicate. The amount of Ca removed by precipitation ranged from 62 to 97%. The most important parameters affecting Ca reduction were pH, Ca/P ratio, and the pH × Ca/P interaction, all of them with a P-value <0.01. Temperature and time did not have a significant effect on Ca reduction (P-value >0.05). Optimal conditions for Ca removal were found at pH ≥9 and a Ca/P ratio of 0.55. Under these conditions, Ca and Mg were reduced by 97% and 85%, respectively. This work will help identify a method for improving the processing behavior of acid whey, which will benefit the dairy industry and will reduce the environmental impact of this dairy byproduct.