Background: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. Patients and methods: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2)were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4°F) or related symptoms. Results: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia,and pyrexia was not statistically significantly associated with treatment outcome. Conclusions: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia,and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.