Chronic lymphocytic leukemia (CLL) B cells that express unmutated immunoglobulin heavy-chain variable region genes (IgV_H) generally express ZAP-70, in contrast to normal B cells or most CLL cases with mutated IgV_H. Following IgM ligation, ZAP-70⁺ CLL cells had significantly higher levels of phosphorylated p72^Syk, BLNK, and phospholipase-Cγ (PLCγ) and had greater[Ca²⁺]_i flux than did ZAP-70–negative CLL cases, including unusual ZAP-70–negative cases with unmutated IgV_H. IgM ligation of ZAP-70–negative CLL B cells infected with an adenovirus vector encoding ZAP-70 induced significantly greater levels of phosphorylated p72^Syk, BLNK, and PLCγ and had greater[Ca²⁺]_i flux than did similarly stimulated, noninfected CLL cells or CLL cells infected with a control adenovirus vector. We conclude that expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgV_H.