Superconductor films on semiconductor substrates draw much attention recently since the derived superconductor-based electronics have been shown promising for future data process and storage technologies. By growing atomically uniform single-crystal epitaxial Pb films of several nanometers thick on Si wafers to form a sharp superconductor-semiconductor heterojunction, we have obtained an unusual giant magnetoresistance effect when the Pb film is superconducting. In addition to the great fundamental interest of this effect, the simple structure and compatibility and scalability with current Si-based semiconductor technology offer a great opportunity for integrating superconducting circuits and detectors in a single chip.