BACKGROUND ζ‐Chain associated protein (ZAP)‐70 has been proposed as a surrogate marker for immunoglobulin heavy‐chain variable region (IgVH) mutation in chronic lymphocytic leukemia (CLL), but it is still not clear whether it is an independent prognostic factor. METHODS The authors evaluated ZAP‐70 expression by flow cytometry in 201 untreated patients and correlated ZAP‐70 levels with CD38 expression, genetic abnormalities detected by fluorescence in situ hybridization (FISH), and the time from diagnosis to first treatment. RESULTS Fifty‐seven patients (28%) were positive for ZAP‐70 (≥ 20%). Positive ZAP‐70 status was associated with advanced disease stage, atypical morphology, CD38‐positive status, trisomy 12, del(6q), or no detectable abnormalities; negative ZAP‐70 status was correlated with del(13q) as a sole abnormality. The treatment‐free interval (TFI) was 17.7 months for ZAP‐70‐positive patients and 44.6 months for ZAP‐70‐negative patients (P < 0.001). Multivariate analysis in 117 patients identified advanced stage, CD38 ≥ 7%, and the absence of del(13q) as a sole abnormality as independent factors for short TFI. Excluding FISH, ZAP‐70 status acquired independent prognostic value along with CD38 status. The authors proposed a risk model that combines ZAP‐70 and CD38 to identify patients who are likely to progress. When both markers were positive, the TFI was 12 months; when both were negative, the median TFI was 54 months; a median TFI of 26 months was observed in patients who had discordant results (P < 0.00001). CONCLUSIONS The current findings suggested that both ZAP‐70 and CD38 should be tested prospectively in all patients with early‐stage CLL. Cancer 2005. © 2005 American Cancer Society. The authors investigated the prognostic significance of ζ‐chain associated protein (ZAP)‐70, as determined by flow cytometry, in relation to other known prognostic factors to predict the time to first treatment in a cohort of 201 previously untreated patients with chronic lymphocytic leukemia (CLL). ZAP‐70 (cut‐off point, 20%) and CD38 (cut‐off point, 7%) showed complementary prognostic value. A risk model is proposed that combines both markers to classify patients with CLL into 3 subgroups with significantly different time to first treatment or treatment‐free interval (TFI): ZAP‐70‐positive/CD38‐positive: TFI, 12 months; ZAP‐70‐positive/CD38‐negative or ZAP‐70‐negative/CD38‐positive: TFI, 26 months; and ZAP‐70‐negative/CD38‐negative: TFI, 54 months.