Complicated urinary tract infections denote an important research field for new antibiotics against Gram-negative pathogens. There is, however, increasing concern that this disease entity is too vaguely defined, leading to heterogeneous study populations and risk of bias. We analysed researchers’ adherence to the US Food and Drug Administration (FDA) guidance on complicated urinary tract infection and assessed risk of bias using a three-step procedure: literature review of full-text articles on complicated urinary tract infection; assessment of the importance of risk factors for treatment failure, including statistical evaluation of how patients with risk factors might skew treatment effects; and a Delphi consensus process in a multidisciplinary group. Our evaluation showed poor adherence to FDA guidance on complicated urinary tract infection and significant heterogeneity in the reporting of study, patient, and pathogen characteristics, leading to a high risk of bias when interpreting and comparing study findings. We therefore question the concept of complicated urinary tract infection as a meaningful entity with its own study guidance.