In this study we show that i) the SIRPα checkpoint suppresses ADP responses to obinutuzumab by NLCs from CLL patients, ii) SIRPα signaling operates via a Shp1/SYK axis, and, iii) SIRPα-mediated suppression does not affect PI3K/p110δ/AKT–dependent ADP. The gene discussed is SIRPA; the disease is B-cell chronic lymphocytic leukemia.