BackgroundTraditional pain management after total knee arthroplasty (TKA) relies heavily on opioids. Although there is evidence that in-hospital multimodal pain management (MMPM) is more effective than opioid-only (OO) analgesia, there has been little focus on postdischarge pain management. The hypothesis of this study was that MMPM after TKA would reduce pain scores and opioid consumption in the 30-day period after hospital discharge. MethodsThis is a prospective, 2-group, comparative study with a provider cross-over design comparing a 30-day OO prn regimen with a MMPM regimen and opioid medications prn. The primary outcome measure was visual analog scale pain score and opioid-related side effects. Secondary outcome measures included morphine milligram equivalents consumed, failure of the protocol, and opioid refills. ResultsThere were 216 patients included in the trial, with final data available for 143. There was no clinically meaningful difference in visual analog scale score between the 2 groups at any time. Average opioid consumption at 30 days was 582.5 and 386.4 morphine milligram equivalents for the OO and MMPM cohorts, respectively (P = .0006). Average number of opioid pills consumed at 30 days was 91.8 and 60.4 for OO and MMPM cohorts, respectively (P = .0004). ConclusionA 30-day postdischarge multimodal pain regimen reduced opioid use after TKA while maintaining a similar level of pain control as the OO regimen. OO regimens are at an increased risk of needing additional medications to control pain. Level of EvidenceLevel II. Registry Namewww.clinicaltrials.gov. Trial NumberNCT04003350.