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. Here, PIK3CD is linked to B-cell chronic lymphocytic leukemia.