Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. In the past years, new therapeutic approaches (e.g., ibrutinib or venetoclax) have been established and greatly improved treatment of CLL. However, complete control or cure of the disease have not been reached so far. Thus, reliable prognostic markers are an imperative for treatment decisions. Recent studies have revealed an essential role for B cell receptor (BCR) signaling in the pathogenesis, prognosis, and therapy of CLL. A heterogeneous response to receptor stimulation with anti-IgM treatment culminating in different calcium flux capabilities has been demonstrated by several authors. However, the methods employed have not reached clinical application. Here, we report on a flow cytometry-based assay to evaluate calcium flux capabilities in CLL and demonstrate that compromised BCR signaling with diminished calcium flux is associated with a significantly better clinical outcome and progression free survival. In summary, our data strongly support the role of compromised BCR signaling as an important prognostic marker in CLL and establish a novel diagnostic tool for its assessment in clinical settings.