The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgVH) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgVH but lack expression of ZAP-70. We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgVH gene. We then investigated the association between the results and the time from diagnosis to initial therapy. We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgVH gene (71 percent), but in only 24 of the 143 patients with a mutated IgVH gene (17 percent, PIgVH gene (2.8 years) was not significantly different from the median time in those who had a mutated IgVH gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70–negative CLL cells who had either mutated or unmutated IgVH genes (PIgVH gene and 7.1 years in those with an unmutated IgVH gene (PIgVH gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.