Introduction: Healthcare-associated infections are an established challenge in public hospitals in Greece, with rates higher than the EU average. During the pandemic, managing HAIs has been even more challenging, with increased recorded rates coupled with high morbidity, mortality and overall workplace pressure.  Aim: To assess the incidence and risk factors associated with HAIs in patients of a COVID-19 department, to establish their role in the hospital outcome and to organize targeted preventive measures. Methodology: Observational study and prospective review over a 1-year period.  Multiple regression analysis was used to identify risk factors. Semi-structured interviews within the multidisciplinary team were used to identify facilitators and barriers to safe practices. Results: Our sample consisted of 480 patients with an average age of 64, from the community (94%) and with co-morbidities (62%), with average length of stay of 8 days and 17% being immunosuppressed due to illness, cancer or medication. HAIs prevalence was 8%, mostly respiratory, urinary tract and blood stream infections. Klebsiella pneumoniae, Acinetobacter baumanii and E coli were most frequently isolated. Length of stay and age were significant risk factors for HAI and admission for over 7 days and age above 80 for death. Outcome data discussed in interviews with medical, nursing and physiotherapy staff highlighted the role of adequate staffing and effective communication in infection prevention and management. Conclusion: HAIs significantly affect mostly the elderly and frail patients. Efforts for effective prevention need to focus on interdisciplinary collaboration for prevention, monitoring and managment.