Persons with opioid use disorder (OUD) often experience anhedonia and demoralization, yet there is relatively little research on the pathophysiology of anhedonia and demoralization in OUD treatment and recovery. In the current study, persons maintained on methadone (N = 29) underwent a natural reward-cue paradigm during functional near-infrared spectroscopy (fNIRS) imaging. Natural reward cues included highly palatable food, positive social interactions (e.g., a happy family at the dinner table), and emotional intimacy (e.g. couples embracing or kissing, but no erotic images). Participants also self-reported symptoms of anhedonia on the Snaith-Hamilton Pleasure Scale (SHPS) and demoralization on the Demoralization Scale II (DS-II). Participants who reported clinically-significant anhedonia on the SHPS displayed decreased neural activity in the right prefrontal cortex (PFC) in response to natural reward cues (F(1,25) = 3.612, p = 0.027, η = 0.302). In linear regression models of positive social cues, decreased neural activity in the right VMPFC was associated with increased SHPS total score (F(1,27) = 7.131, R = 0.209, p = .013), and decreased neural activity in an area encompassing the right lateral VMPFC and DLPFC was associated with increased DS-II total score (F(1,27) = 10.641, R = 0.283, p = 0.003). This study provides initial evidence that the prefrontal cortex is involved in the pathophysiology of anhedonia and demoralization in persons in recovery from OUD. Anhedonia and demoralization are important treatment outcomes that should be queried along with a constellation of physical and mental health outcomes, to assess areas of needed improvement in methadone maintenance and other OUD treatment modalities.Copyright © 2020 Elsevier Ltd. All rights reserved.