Background: BTK is an attractive target in CLL. Ibrutinib (IB), a first in class irreversible BTK inhibitor (BTKi), abrogates important survival signals in CLL by proximally blocking multiple pathways. Despite IB’s ability to produce remissions in patients, resistance can occur via mutation at its BTK binding site. IB also inhibits ITK, limiting antibody dependent cytotoxicity (ADCC) and the efficacy of antibody therapy. Here we demonstrate the potential utility of a novel BTKi, GDC-0853, which does not rely upon the C481 site of BTK and lacks ITK inhibition. Methods: In vitro studies used freshly purified B cells from primary CLL samples treated with BTKi at a concentration of 1µM. Signaling was investigated by immunoblot while viability, CD86 expression, and migration were measured by flow cytometry. Natural killer (NK) cell ADCC was measured by chromium release. Results: GDC-0853 reduced the activation of BTK and its downstream targets PLCg2, AKT, and ERK following αIgM stimulation (79%, 44%, 60%, and 86% respectively; p ≤ 0.05). GDC-0853 modestly decreased CLL viability and abrogated the protective effect of stromal co-culture (10% viability decrease p = 0.012). Increases in CD86 expression induced by CpG were decreased 40% following treatment with GDC-0853 (p = 0.001). We also found that GDC-0853 diminished CXCL12 induced chemotaxis by 51% (p = 0.028). Unlike IB, GDC-0853 inhibited signaling of both WT and C481S mutated BTK in transfected HEK293T cell lines. Also unlike IB, GDC-0853 preserved NK cell ADCC with clinical αCD20 antibodies. While IB significantly decreased ADCC with rituximab, ofatumumab, and obinutuzumab, there was no change in NK cell mediated ADCC following treatment with GDC-0853. Conclusions: GDC-0853 represents an exciting development in BTK targeted therapy. Agents like this which bind outside BTK C481 may circumvent resistance to IB. Additionally, GDC-0853 may also enable effective combinations with antibody therapies, potentially prolonging remissions. Given these compelling data we believe further clinical exploration of GDC-0853 as monotherapy and in combination with αCD20 antibody therapies is justified.