Friedrich Nietzsche (1844-1900), a preeminent German philosopher, was crushed by mental illness at the age of 44. In ac-cordance with a prevailing paradigm of the time, this was diagnosed as tertiary syphilis, a diagnosis that endured for more than a century despite no evidence for it. In the last two decades, several alternative diagnostic hypotheses, such as bipolar affective disorder, schizophrenia, brain tumor, frontotemporal dementia and rare genetic conditions have been proposed instead. The aim of this study was to discuss them critically against the historical and epistemological backdrop and to suggest the most likely diagnosis. An in-depth study of Nietzsche's biography, his published and unpublished writings, his correspondence, accounts of his friends and colleagues and an examination of the fluctuating pattern of his creativ-ity and handwriting has been undertaken for this purpose. Criteria for a credible and meaningful posthumous diagnostic hypothesis are also outlined. Diagnoses of organic conditions with established verification tests, such as brain tumor or genetic disorders, are rejected on the basis of undeliverability of such tests. Diagnoses of schizophrenia and frontotem-poral dementia are discarded due to the lack of leading symptoms and the biographical impossibility. The overall clinical picture of Nietzsche's mental illness, based on historical sources, points towards bipolar disorder with onset in young adulthood. It was probably followed by multi-infarct dementia. Being posthumous, the diagnosis remains hypothetical. The form and the content of Nietzsche's writings may have been influenced by bipolar disorder, and this would have bearing on the interpretation of his philosophy.(Cite this article as: Cybulska EM. Nietzsche and bipolar disorder: a critical evaluation of diagnostic hypotheses from a his-torical and epistemological perspective. Minerva Psychiatry 2023;64:80-90. DOI: 10.23736/S2724-6612.22.02332-6)