OBJECTIVES: Two epidemics in the United States are related: opioid drug injection and hepatitis C virus (HCV) infection. This study quantifies the relationship between illicit/prescription drug misuse and HCV infection in 3 population generations: baby boomers (born 1945-1965, inclusive), pre-baby boomers, and post-baby boomers. METHODS: This retrospective study included prescription drug consistency (March-December 2015) and HCV (2011-2015) patient test results performed at a large national clinical reference laboratory. HCV positivity, drug use consistency/inconsistency with prescribed drug information, type of inconsistent use, and inconsistent use of individual drug classes were assessed. RESULTS: This study evaluated 39,231 prescription drug monitoring and HCV sets of test results from 18,410 patients. Of these patients, 25.1% tested positive for HCV and 57.3% demonstrated drug test results that were inconsistent with the prescribed medication(s). The types of drug test inconsistency differed substantially between HCV-positive and -negative patients, particularly testing positive for both non-prescribed drugs and prescribed drugs. Specimens from HCV-positive baby boomer and post-baby boomers demonstrated non-prescribed use of opioids and many other drug classes more often than from HCV-negative patients. CONCLUSIONS: The rates of inconsistent drug test results and types of drugs misused suggest that HCV-positive patients are more likely than HCV-negative patients to display high-risk behavior, even beyond opioid use. This difference is most pronounced in the post-baby boomer generation. Healthcare professionals should consider these patterns and how they differ by generation when monitoring for both prescription and illicit drugs, the results of which can impact treatment decisions including prescribing analgesics.