The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p < 0.001). This study shows that the evidence of lymphocytopenia prior to chemotherapy is associated with a lower efficacy of treatment in terms of objective tumor regression rates in patients with metastatic solid tumors, and suggests that the action of chemotherapy may depend at least in part on an interaction with the antitumor immunity. Pretreatment lymphocyte count may represent a new, simple biological marker to be taken into consideration by oncologists in the chemotherapeutic treatment of metastatic cancer.