Human intestinal spirochaetosis is caused by the colonisation of the luminal membrane of the colon and rectum by anaerobic spirochaetes belonging to the genus Brachyspira. The common method used for its diagnosis is routine haematoxylin and eosin staining of colonic and rectal biopsy samples. The clinical spectrum of human intestinal spirochaetosis is heterogeneous, ranging from asymptomatic colonisation to symptoms such as chronic mucosal diarrhoea, rectal bleeding, and abdominal pain. In this Grand Round, we present a detailed report of the endoscopic and histological evaluation and clinical and therapeutic management of an immunocompetent patient with chronic watery diarrhoea caused by intestinal spirochaetosis followed by infection with Giardia lamblia. The initial histological picture mimicked other causes of chronic diarrhoea, such as inflammatory bowel disease, microscopic colitis, and eosinophilic enterocolitis, leading to a delay in diagnosis and treatment. A full course of metronidazole led to the remission of symptoms and to the complete eradication of pathogens as shown by the follow-up histological assessment. This case report highlights the need to consider intestinal spirochaetosis in the differential diagnosis of chronic watery diarrhoea, even when immunodeficiency or other probable risk factors are not present.