Bruton’s tyrosine kinase (BTK) inhibitors are key drugs in the frontline therapy of chronic lymphocytic leukemia. Invasive fungal infection is a well-documented adverse event in patient treated with first-generation BTK inhibitors. This rare but severe adverse event has been described in several case-reports and series in patients receiving ibrutinib, particularly invasive aspergillosis, especially of cerebral location. Second-generation BTK inhibitors such as acalabrutinib are more selective for BTK and are as effective and better tolerated than ibrutinib. Only six case-reports have described an opportunistic fungal infection occurring with second-generation BTK inhibitors. Here, we report the case of a patient who developed fatal invasive pulmonary and cerebral aspergillosis while being treated with acalabrutinib.