Four hundred and thirty eight patients undergoing inpatient primary TKA at 11 centers were randomized to receive 4 mg (n = 146), 8 mg (n = 147), or 16 mg (n = 145) of intraoperative IV dexamethasone, all within an identical multimodal analgesia/anesthesia protocol including neuraxial anesthesia, adductor canal block, periarticular injection, and standardized oral analgesics. The primary outcome was cumulative opioid consumption in oral morphine milligram equivalents (MME) over the first 48 hours postoperatively. Secondary outcomes included daily opioid use to 7 days, pain at rest and with activity, nausea scores, vomiting episodes, sleep duration, postoperative day 1 (POD1) glucose, length of stay, and 90-day complications. Outcomes were assessed with a 7-day patient diary and chart review through 90 days. Overall, the results of the study revealed that 16 mg IV dexamethasone modestly reduced early opioid consumption (particularly vs 8 mg), improved pain at rest and reduced vomiting within 24 hours, but increased POD1 glucose in a dose-dependent fashion without increasing short-term complication rates. These findings suggest that 16 mg may be the most efficacious dose for early postoperative comfort in otherwise well-controlled patients, while lower doses may be preferable in patients at higher risk from hyperglycemia.