Abstract Background In common with many countries, Ireland has seen an increasing trend in the number of clinical trials conducted over the past few years. Yet, as elsewhere, trialists in Ireland face several problems and barriers in the starting-up of clinical trials. These barriers impede trial activity significantly, with consequent impacts on patient care. It is critical to understand these issues, to develop approaches to facilitate trial start up. This study identifies the challenges in conducting clinical trials in Ireland and specifically the contractual, ethical, logistical, and regulatory barriers that hinder the start-up of investigator-led trials in Ireland. Methods Data for this study were collected in two stages. In the first stage, a survey was conducted among trialists in Ireland. A total of 44 trialists responded to the survey, and information was collected about their experience in conducting clinical trials, the scale and nature of their most recently completed trial, and the details of specific barriers they encountered during the starting-up of the trial. In the second stage, nine semi-structured interviews were conducted with the awardees of 2018 Irish Health Research Board’s Definitive Intervention Feasibility Award. These interviews facilitated a deeper exploration of issues and problems in conducting clinical trials in Ireland. Results This study identified several issues and bottlenecks in starting-up clinical trials in Ireland with contracts and ethical approval cited as the major issues. The data shows that site identification and activation was also problematic in some cases. Several respondents reported difficulties in accessing dedicated time for protocol development and believe that support in this area can be greatly beneficial. It was reported that availability of skilled staff members like statisticians and data managers was as an issue, especially for small trials. Conclusion This study found that several factors impact trial initiation and progression in Ireland. Delays associated with obtaining contract and ethics approval are perceived as major barriers. Specialist supports in areas such as ethics and regulatory affairs and availability of specialised staff members in areas such as statistics and data management are key actions to enable enhanced clinical trial activity in Ireland.