T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory checkpoint receptor that negatively regulates T cell responses. CD226 competes with TIGIT for binding to the CD155 ligand, delivering a positive signal to the T cell. Here we studied expression of TIGIT and CD226 in a cohort of 115 chronic lymphocytic leukemia (CLL) patients and report expression of TIGIT and CD226 by leukemic cells. By devising a TIGIT/CD226 ratio, we showed that CLL cells favoring TIGIT over CD226 are typical of a more indolent disease, while those favoring CD226 are characterized by a shorter time-to-first-treatment and shorter progression-fee survival after first treatment. TIGIT expression was inversely correlated to the B cell receptor (BCR) signaling capacity, as determined by studying BTK phosphorylation, cell proliferation and IL-10 production. In CLL cells treated with ibrutinib, where surface IgM and BCR signaling capacity are temporarily increased, TIGIT expression was downmodulated, in line with data indicating transient recovery from anergy. Lastly, cells from Richter syndrome patients were characterized by high levels of CD226, with low to undetectable TIGIT, in keeping with their high proliferative drive. Together, these data suggest that TIGIT contributes to CLL anergy by downregulating BCR signaling, identifying novel and actionable molecular circuits regulating anergy and modulating CLL cell functions.