Tumor suppressor function of Btk is not dependent on its kinase activity. Kaplan-Meier tumor-free survival estimates for SLP-65^- (n = 123), Btk^-SLP-65^- (n = 107), and K430R-Btk mice on the Btk^-SLP-65^- background (n = 51). Tumor-free survival in Btk/SLP-65 double-deficient mice was significantly reduced compared with SLP-65^- mice (P < .00001, by log-rank) and to K430R-Btk/SLP-65^- mice (P < .0008). Tumor-free survival in the SLP-65^- and K430R-Btk/SLP-65^- groups of mice was not significantly different.