Targeted memory reactivation (TMR) during sleep improves memory consolidation. However, it is still unknown whether TMR also benefits memory in real-life conditions. We tested whether TMR during sleep enhances Dutch-German vocabulary learning when applied during multiple nights at home in an unsupervised fashion. During 3 consecutive nights, 66 healthy young participants used an mp3-player to play Dutch words during sleep, without any control of sleep or awakenings by tones (unsupervised TMR). Unsupervised TMR benefitted overall memory scores only in a subgroup of participants, who reported no disturbances by TMR during sleep. Participants who reported general disturbances of sleep showed no benefit, while TMR specifically impaired memory in a third group who reported specific disturbances by the played words during sleep. Separate analysis per night indicated that memory benefits by TMR were significant in the entire sample in the third night only. Our results indicate that sleep disturbances and habituation might be critical factors for the success of unsupervised TMR in a home setting. Habituation to the TMR process as well as automatic sleep monitoring and avoidance of auditory-induced awakenings might be a precondition to successful application of TMR to language learning in real-life.