<p>A subset of individuals without a history of prolonged or problematic opioid use demonstrate attenuated subjective responses to orally administered opioids despite physiological and analgesic responses. This phenotype may confer elevated risk for greater analgesic requests and physiologic dependence, but it is unclear if this is driven by differences in route of administration. This study evaluated responses to cumulative dosing of parenteral hydromorphone, versus placebo, in persons without a history of significant opioid use to further identify and characterize this subgroup. Individuals without opioid use disorder (<i>N</i> = 82) were exposed to a cumulative hydromorphone dosing procedure, during which they completed measures of subjective effects and were assessed for physiological opioid responses. Linear mixed effects regressions were used to examine changes in subjective and physiological measures as a function of responder phenotype, drug condition, and time. Approximately 31.7% of the sample were classified as Opioid Non-Responders. These individuals had attenuated changes in subjective responses to hydromorphone relative to other participants, despite equivalent physiological responses. Race and sex did not predict Opioid Responder status. These findings confirm the presence of a “Opioid Non-Responder” phenotype for the first time in the context of a cumulative, parenteral dosing paradigm. Further research is warranted to elucidate the clinical implications and potential risk or protective factors underlying this phenotype.</p>