OBJECTIVES: Abuse of prescription opioid medications through tampering, such as the chewing or crushing of pills, is associated with greater healthcare use.  This study was conducted to assess the economic cost of such tampering in the United States.  METHODS: Participants from the US National Health and Wellness Survey were recontacted for an online survey assessing use, misuse, and abuse of prescription opioid medications.  All measures were self-reported.  Abuse was defined as taking prescription opioid medication for the purpose of getting high in the prior 3 months, and use of the medication in any form other than the original was considered tampering.  Direct medical costs were estimated by applying unit costs to self-reported healthcare visits. Unit costs were sourced from the Truven Market Scan (TMS) database, and the analysis was repeated using unit costs from the Medical Expenditure Panel Survey (MEPS).  Respondents who reported abuse of prescription opioids through tampering were compared to those who reported abuse without tampering.  Costs were compared using bivariate statistics as well as generalized linear models (GLMs) to adjust for confounders. RESULTS: Those who abused through tampering had significantly higher estimated healthcare costs during the 3-month recall period, with mean (unadjusted) incremental cost of $18,814 using TMS unit costs (p<0.001).  This included higher mean costs for non-opioid-related medical visits ($11,944, p<0.001), opioid-related medical visits ($6,567, p<0.001), and drug rehabilitation costs ($303, p<0.001). Median total incremental costs were also higher by $3,803.  GLMs indicated increased total direct costs with tampering after adjusting for confounders (p<0.001).  Conclusions were similar using MEPS unit costs. CONCLUSIONS: Tampering with prescription opioid medications in order to get high is associated with significantly increased medical costs compared to those who abuse without tampering.  Efforts to reduce tampering, such as the use of abuse-deterrent formulations of prescription opioid medications, may provide net healthcare savings.