In a time of limited resources, but increased complexity and demand, innovation presents a pathway to improve quality and efficiency in the provision of healthcare in the National Health Service (NHS) in Wales. There is little scarcity in the availability of quality innovations to the NHS, but there is a clear gap in the ability of the organisation to effectively adopt and spread these innovations into wider use. Research into the adoption of innovations across multiple disciplines has been extensive. Numerous influences have been investigated via mainly quantitative approaches that utilise an array of technology adoption theories. This study explored the adoption of innovation in healthcare in Wales via a pragmatic mixed methods approach using the Technology-Organisation-Environment framework as a theoretical basis. Semi-structured open-ended interviews were conducted with participants experienced in healthcare innovation in Wales. Findings were analysed by a combination coding approach and content analysis. Forty-four factors of influence were discovered, including sixteen novel factors that were not identified in relevant literature. The high importance of individuals and the interactions between people was easily apparent. Therefore, the conceptual framework of ‘People-Organisation-Environment-Technology’, or the ‘POET’ framework, was developed. Theoretical support for this was provided by the Socio-technical systems theory, which acknowledges the importance of people in the social subsystem of an organisation. The POET framework builds upon previous theory by adding the relative levels of importance of and overlap between the four contexts. Second stage analysis assessed the relative importance of factors, their interrelationships, and their propensity to act as barriers or enablers to adoption. The POET framework embraces the complexity in innovation adoption in Wales and is effective for investigating and analysing cases in this setting, and has the potential for generalisability. The findings indicate that NHS Wales should invest in and investigate the influence of people to support innovation adoption.