Background: While the use of prescribing safety indicators (PSI) can reduce potentially hazardous prescribing, there is a need to identify actionable strategies for the successful implementation and sustainable delivery of PSI-based interventions in general practice. Aim: To identify strategies for the successful implementation and sustainable use of PSI-based interventions in routine primary care. Design & setting: Qualitative study in primary care settings across England. Method: Anchoring on a complex pharmacist-led IT-based intervention (PINCER) and clinical decision support (CDS) for prescribing and medicines management, a qualitative study was conducted using sequential, multiple methods. The methods comprised documentary analysis, semi-structured interviews, and online workshops to identify challenges and possible solutions to the longerterm sustainability of PINCER and CDS. Thematic analysis was used for the documentary analysis and stakeholder workshops, while template analysis was used for the semi-structured interviews. Findings across the three methods were synthesised using the RE-AIM (reach, efficacy, adoption, implementation, and maintenance) framework. Results: Forty-eight documents were analysed, and 27 interviews and two workshops involving 20 participants were undertaken. Five main issues were identified, which aligned with the adoption and maintenance dimensions of RE-AIM: fitting into current context (adoption); engaging hearts and minds (maintenance); building resilience (maintenance); achieving engagement with secondary care (maintenance); and emphasising complementarity (maintenance). Conclusion: Extending ownership of prescribing safety beyond primary care-based pharmacists, and achieving greater alignment between general practice and hospital prescribing safety initiatives, is fundamental to achieve sustained impact of PSI-based interventions in primary care.