Detection of functional, circulating T cells and NK cells may serve as a clinical test for the selection of individuals who can benefit from immunotherapy. Incidence of the T‐cell receptor zeta (TCRζ) chain within these populations appears to correlate with adequate effector cell function. In patients with advanced malignancy, the absence or reduced expression of ζ chain has been documented. Flow cytometric analysis in the present study revealed a significant reduction in ζ chain expression in peripheral blood lymphocytes (PBL) of 14 of 22 prostate cancer patients (P < 0.000001) as compared to normal donors, apparent in both T cells (CD3+, CD4+, CD8+), and NK (CD16+) cells. Compared to normal donor PBL, patient PBL cultured in the presence of CD3 and CD28, also demonstrated reduced expression of CD69 and/or CD25, and in some cases, failed to activate at all. Furthermore, evidence of cell proliferation in activation‐stimulated patient PBL was muted: average PCNA positivity equaled 14%, a marked difference from what was observed in normal donors (P < 0.0002). In 8 of 16 samples of PBL, where ζ expression was originally low, ζ levels returned to the normal range after 48 hour culture in serum‐free medium, suggesting that the loss of ζ is reversible and may be caused by a tumor‐derived substance. These data support the premise that monitoring the expression of ζ in a cancer patient may provide a unique insight into the immune status and functionality of the individual, with the potential to redirect or augment therapies and ultimately alter prognosis. Cytometry 32: 109–119, 1998. © 1998 Wiley‐Liss, Inc.