Background The co-administration of multiple drugs (polypharmacy) is the single most common cause of adverse drug events in the older population, and residents of long-term care facilities (LTCFs) are at particularly high risk of medication harm. 'Deprescribing' - the withdrawal of an inappropriate medication with goal of managing polypharmacy and improving outcomes - may improve the quality of life of LTCF residents. The RELEASE study sought to explore perceptions of medication use and the concept of deprescribing in LTCFs. Methods Focus groups and interviews were conducted with General Practitioners (GPs), pharmacists, nursing staff, residents and their relatives within three LTCFs in the Illawarra-Shoalhaven region of NSW, Australia. Audiotapes were transcribed verbatim and, using the Integrative Model of Behaviour Prediction as a framework, thematic analysis of transcripts was conducted using QSR NVivo 10. Results Participants acknowledged the burden of too many medications (time to administer, physical discomfort, cost), yet displayed passivity towards medication reduction. Residents and relatives lacked understanding of medicine indications or potential harms. Willingness to initiate and accept medication change was dependent on the GP, who emerged as a central trusted figure. GPs preferred 'the path of least resistance', signalling systems barriers (poor uniformity of LTCF medical records, limited trained LTCF personnel); time constraints (resident consultations, follow-up with specialists and family); and the organisation of care (collaborating with LTCF staff, pharmacists and prescribing specialists) as obstacles to deprescribing. Conclusions Targeted engagement is required to raise awareness of the risks of polypharmacy in LTCFs and encourage acceptance of deprescribing amongst residents and their relatives. GPs are integral to the success of deprescribing initiatives within this sector.