In this real-world retrospective study of patients with CLL/SLL treated at UCSF, outcomes with next-generation BTK inhibitors zanubrutinib and acalabrutinib were compared using adjusted analyses of time to next treatment and overall survival. Despite patients receiving zanubrutinib having more high-risk features and comorbidities, zanubrutinib was associated with a lower risk of starting subsequent therapy and a trend toward improved survival compared with acalabrutinib.