In the United Kingdom, pharmacist and nurse independent prescribers are responsible for both the clinical assessment of and prescribing for patients. Prescribing is a complex skill that entails the application of knowledge, skills and clinical reasoning to arrive at a clinically appropriate decision. Decision-making is influenced and informed by many factors. This study, the first of its kind, explores what factors influence pharmacist and nurse independent prescribers during the process of clinical reasoning. A think-aloud methodology immediately followed by a semi-structured interview was conducted with 11 active nurse and 10 pharmacist independent prescribers working in secondary care. Each participant was presented with validated clinical vignettes for the think-aloud stage. Participants chose the clinical therapeutic areas for the vignettes, based upon their self-perceived competencies. Data were audio-recorded, transcribed verbatim and a constant-comparative approach was used for analysis. Influences on clinical reasoning were broadly categorised into themes: social interaction, intrinsic and contextual factors. These themes showed that intrinsic, socio-cultural and contextual aspects heavily influenced the clinical reasoning processes of prescribers. For example, prescribers were aware of treatment pathways but chose to refer patient cases to avoid making the final prescribing decision. Exploration of this behaviour in the interviews revealed that previous experience and attitudes such as confidence and cautiousness associated with responsibility were strong influencers within the decision-making process. In addition, strengthening the professional identity of prescribers could be achieved through collaborative work with interprofessional healthcare teams to orient their professional practice from within the profession. Findings from this study can be used to inform the education, training, and practice of independent prescribers to improve healthcare services by improving their professional and interprofessional development.