Background Health information exchange (HIE) systems, that are computer-based tools used by healthcare providers for secure access to share patient's medical information electronically, seem to help reduce the use of specific resources and improve the quality of care. This highlights the importance of this issue in the Public Health sector. This research goal is to identify barriers and facilitators perceived by general practitioners (GPs) when using an HIE system in a Southern Switzerland area. Methods we performed a qualitative study using semi-structured interviews, interviewed 10 GPs, randomly selected among some 500 HIE system local users and analysed interview transcripts using thematic content analysis with an abductive approach (a mix of deductive and inductive approaches). Results findings showed the following key facilitators: a) perception of dealing with a secure system; b) possibility of delegating management to secretaries and healthcare assistants; c) technical support and training; d) high quality of the information exchange; e) positive impact on clinical practice; and f) regional context. However, major challenges persist, and GPs reported the following main barriers to using an HIE system: a) frequent lack of all patient information needed; b) no effective workflow improvements; c) lack of some technical features. Conclusions We propose four recommendations based on findings: 1. Future initiatives should focus on developing HIE systems giving GPs access to all possible patient medical information; 2. Crucial data privacy and security issues should never be overlooked; 3. Technical and workflow improvements should particularly consider the socio-technical nature of HIE systems; 4. Much attention needs to be paid to the importance of relationships between health care providers and between these and local health institutions when implementing HIE systems. Key messages This study filled a research gap as it is the first that tackles HIE system barriers and facilitators in Ticino. When information sharing for clinical practice focuses on improving the quality and costs of healthcare, GP's trust in HIE system security is crucial.