INTRODUCTION: Polypharmacy is increasing among older individuals worldwide. Deprescribing has been suggested as a strategy to reduce polypharmacy, but it has had a limited impact. OBJECTIVE: This study investigated the facilitators and barriers to deprescribing in older adults, as perceived by primary care general practitioners, focusing particularly on factors influencing deprescribing in frail individuals. METHODS: A qualitative approach was employed and semistructured interviews were conducted between 9 April and 29 May 2024 with a sample of 30 general practitioners working in primary care facilities in Crete, Greece. The interviews were recorded and transcribed verbatim. Thematic analysis was performed on the basis of the Theoretical Domains Framework. RESULTS: Several barriers to deprescribing were revealed, including a lack of expertise and motivation, inadequate communication skills, time constraints, and negative beliefs toward deprescribing held by physicians and patients. The lack of an established role for general practitioners in primary care, the absence of a national initiative targeting polypharmacy, and the influence of pharmacists and pharmaceutical representatives were highlighted as challenges. The identified facilitators included the incorporation of deprescribing recommendations and considerations for frail patients into guidelines, fostering a strong doctor-patient relationship, promoting shared decision-making, facilitating effective collaboration with caregivers, and utilizing nonpharmacological therapy. CONCLUSIONS: General practitioners encounter both barriers and facilitators when making deprescribing decisions for older adults, particularly those with frailty syndrome. Researchers and policymakers can use the findings of this research to guide future interventions and promote successful deprescribing practices.