Docetaxel is the standard first-line agent for the treatment of androgen-independent prostate cancer (AIPC). The combination of docetaxel with molecularly targeted therapies may offer the potential to increase the efficacy and decrease the toxicity of cytotoxic chemotherapy for prostate cancer. Previous studies demonstrate activation of the human epidermal growth factor receptor (EGFR) in prostate cancer. Erlotinib is a specific inhibitor of the tyrosine-kinase activity of EGFR. The goal of this study is to determine the anti-cancer activity docetaxel combined with erlotinib for the treatment of elderly subjects with AIPC. This is a multi-institutional Phase II study in patients with histologically confirmed adenocarcinoma of the prostate and age ≥ 65 years. Patients were requred to have progressive disease despite androgen-deprivation therapy as determined by: (1) measurable lesions on cross-sectional imaging; (2) metastatic disease by radionucleotide bone imaging; or (3) elevated prostate specific antigen (PSA). Treatment cycles consisted of docetaxel 60 mg/m2 IV on day 1 and erlotinib 150 mg PO days 1–21. Patients with responding or stable disease after 9 cycles were eligible to continue on erlotinib alone as maintenance therapy. Characteristics of 22 patients enrolled included: median age 73.5 years (range, 65–80); median Karnofsky Performance Status 90 (range 70–100); median hemoglobin 12.1 g/dl (range, 10.0–14.3); median PSA 218.3 ng/ml (range, 9–5754). A median of 6 treatment cycles were delivered per patient (range 1–17). No objective responses were observed in 8 patients with measurable lesions (0%, 95% CI 0–31%). Bone scan improvement and PSA decline was seen in 1 patient (5%, 95% CI 0.1–25%). Five of 22 patients experienced ≥ 50 % decline in PSA (23%, 95% CI 8–45%). Hematologic toxicity included grade 3 neutropenia in 9 patients and neutropenic fever in 2 patients. Common non-hematologic toxicities (≥ grade 3) included fatigue, anorexia, and diarrhea. Docetaxel/erlotinib can be delivered safely in elderly patients with AIPC. Anti-cancer disease activity appears generally comparable to docetaxel when used as monotherapy. Hematologic and non-hematologic toxicity may be increased over docetaxel monotherapy. Prospective randomized studies would be required to determine if the toxicity of docetaxel and erlotinib justifies its use in this setting.