Treatment-refractory giardiasis: challenges and solutions Marco Lalle,1 Kurt Hanevik2,3 1Department of Infectious Diseases, European Reference Laboratory for Parasites, Istituto Superiore di Sanità, Rome, Italy; 2Norwegian National Advisory Unit on Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, Bergen, Norway; 3Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway Abstract: Giardia is the commonest parasitic diarrheal pathogen affecting humans and a frequent cause of waterborne/foodborne parasitic diseases worldwide. Prevalence of giardiasis is higher in children, living in poor, low hygiene settings in developing countries, and in travelers returning from highly endemic areas. The clinical picture of giardiasis is heterogeneous, with high variability in severity of clinical disease. It can become chronic or be followed by post-infectious sequelae. An alarming increase in cases refractory to the conventional treatment with nitroimidazoles (ie, metronidazole) has been reported in low prevalence settings, such as European Union countries, especially in patients returning from Asia. In view of its relevance, we aim in this review to recapitulate present clinical knowledge about Giardia, with a special focus on the challenge of treatment-refractory giardiasis. We propose a working definition of clinically drug-resistant giardiasis, summarize knowledge regarding resistance mechanisms, and discuss its clinical management according to research-based evidence and medical practice. Advances in development and identification of novel drugs and potential non-pharmacological alternatives are also reviewed with the overall aim to define knowledge gaps and suggest future directions for research. Keywords: Giardia duodenalis, giardiasis, drug resistance, treatment failure, antigiardial therapy