Horses kept for recreational riding purposes by a wildlife tourism company in a heavily tsetse fly-infested region of north-western Tanzania were systematically monitored to investigate the occurrence, presentation and management of tsetse-transmitted trypanosomosis. During a 23-month period, 18 clinical cases were diagnosed (Trypanosoma brucei or Trypanosoma congolense were identified) and treated and trypanosomes were implicated of involvement in four deaths. Pyrexia consistently aided early detection (17 cases). Ataxia, weight loss and anaemia were seen in chronic cases and conferred a poor prognosis. Delaying treatment by more than 2 days from the onset of clinical signs led to prolonged disease course and more severe anaemia. Early detection, prompt treatment, thorough post-treatment health monitoring and rigorous prophylactic measures helped keep clinical cases to manageable levels, but re-infection remained a constant, insidious threat.