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Failure of medical treatments can hamper responses to subsequent treatments. It has been suggested that changing the route of drug administration could reduce such negative carry-over effects, but direct evidence for this approach is lacking. We therefore investigated in 211 healthy volunteers whether changes in drug administration route reduce such carry-over effects. A positive or negative treatment history with topical analgesic treatments was induced experimentally in a mock clinical trial setting. Subsequently, a different inert drug was introduced via the same (topical) or another (oral) route of administration and its analgesic efficacy was tested. Changing the route of drug administration induced expectations of positive treatment effects in the subjects but did not actually counteract the negative carry-over effects on treatment efficacy. These findings indicate that learned carry-over effects generalize over time and across routes of drug administration—independent of conscious expectations. Other strategies are needed to prevent negative carry-over effects of treatment failure from influencing the results of subsequent treatment attempts.