Substance abuse can have strong negative impacts on surgical outcomes. Therefore, this study assessed the effects of drug abuse in total knee arthroplasty (TKA) patients. Specifically, we identified revision TKA (RTKA): (1) incidence, (2) causes, (3) time to revision, and (4) patient demographics in patients with a history of drug abuse. The Medicare database within the PearlDiver Supercomputer (Warsaw, IN) was queried to identify 2,159,221 TKAs performed between 2005 and 2012. Drug abuse was subdivided into cocaine, cannabis, opioids, sedatives/hypnotics/anxiolytics (SHA), amphetamines, and alcohol abusers. The effect of drug use on the incidence and cause for RTKA, time to revision, as well as patient demographics were correlated using multivariate, analysis of variance, and regression analyses. There was a significant increase in the number of primary TKAs in cocaine (p = 0.011), cannabis (p < 0.001), opioid (p < 0.001), SHA (p < 0.001), amphetamine (p < 0.001), and alcohol (p < 0.001) users. Amphetamine users had the fastest mean time to revision (691 days, standard deviation: 679 days). At 30-, 90-day, and 6-month postoperative, cocaine had the highest proportion of patients requiring RTKA (7, 12, and 20%, respectively), and at 1-year alcohol abusers (38%, p < 0.001). Infection was the most common cause of revision in all drug abuse/dependent cohorts. Age distributions varied significantly by group for primary TKA (p < 0.001). Comorbidity status was similar in all RTKA patients as determined by comparison of the mean Charlson comorbidity index scores (p = 0.091). Based on these results, drug abuse patients are at increased risk for RTKA. These high-risk patients should, therefore, be appropriately risk stratified and receive comprehensive postoperative pain management.