Our preliminary studies found technetium-99m tetrofosmin (Tc- TF) chest imaging was related to Pgp or MRP1 expression and successfully predict chemotherapy response and in SCLC in human. However, there was no published literature to study relationship of Tc-TF chest images and LRP expression in SCLC patients. Therefore, the aim of this study was to investigate the relationships among Tc- TF accumulation in untreated small cell lung cancer (SCLC), the expression of P-glycoprotein (Pgp), multidrug resistance related protein-1 (MRP1), and lung resistance-related protein (LRP), as well as the response to chemotherapy in patients with untreated SCLC. Thirty patients with SCLC were studied with chest images 15 to 30 minutes after intravenous injection of Tc-TF before chemotherapeutic induction. Tumor-to-background (T/B) ratios were obtained on the static and plantar Tc-TF chest images. The response to chemotherapy was evaluated upon completion of chemotherapy by clinical and radiological methods. These patients were separated into 15 patients with good response and 15 patients with poor response. No significant differences of prognostic factors (Karnofsky performance status, tumor size, or tumor stage) were found between the patients with good and poor responses. Immunohistochemical analyses were performed on multiple nonconsecutive sections of biopsy specimens to detect Pgp, MRP1, and LRP expression. The difference in T/B ratios on the Tc-TF chest images of the patients with good versus poor response was significant. The differences in T/B ratios of the patients with positive versus negative Pgp expression and with positive versus negative MRP1 expression were significant. The difference in T/B ratios of the patients with positive versus negative LRP expression was not significant. We concluded that Tc-TF chest images could accurately predict chemotherapy response of patients with SCLC. In addition, The Tc-TF tumor uptake was related to Pgp or MRP1 but not LPR expression in SCLC.