Chemotherapy resistance is a significant contributor to treatment failure and death in men with hormone-refractory prostate cancer. One unexplored mechanism for drug resistance is the induction of stress response proteins referred to as the glucose-regulated proteins (GRPs). We sought to determine the level of expression of GRP78, the best characterized GRP in lymph node-positive prostate cancer. Archived, paraffin-embedded, radical prostatectomy specimens were obtained from 153 patients with lymph node-positive prostate cancer (stage D1). The level of GRP78 expression was determined by immunohistochemistry. We assessed the expression and specificity of GRP78 immunoreactivity in benign prostatic tissue, prostate cancer, and lymph node metastasis. We correlated the intensity of immunopositivity with prostate cancer recurrence and survival. Whereas immunohistochemical staining demonstrated that all prostate tissue was immunoreactive for GRP78, the intensity of expression was markedly higher in the primary tumor compared with areas of benign epithelium. GRP78 expression was also evident in lymph node metastases although less intensely than in the primary tumor. Patients with strong GRP78 immunoreactivity in the primary tumor are at higher risk for clinical recurrence (relative risk = 2.0, P = .019) and death (relative risk = 1.8, P = .024) than patients with weak GRP78 expression. This finding confirms that GRP78 protein expression is significantly higher in prostate cancer than in benign prostatic tissue. The intensity of expression is significantly associated with survival and clinical recurrence. GRP78 has considerable potential not only as a prognostic indicator but also as a potential therapeutic target.