The purpose of this study was to compare mRNA levels of the cytotoxic lymphocyte (CL) gene products: granzyme B (GB), perforin (P), and fas ligand (FasL) in patients with long-term type 1 diabetes and healthy controls. The objective was to utilize this information to follow patients as they undergo islet cell transplantation at our center and to determine if changes in CL gene transcript levels correlate with graft status. We have measured mRNA levels for CL genes in peripheral blood samples from 65 long-term (>5 years) type 1 diabetes patients and 29 healthy controls. Total RNA was extracted from EDTA anticoagulated peripheral blood samples and reverse transcribed into first-strand cDNA using SuperScript II reverse Transcriptase. Quantitative, real-time PCR was utilized to determine CL gene transcript levels. mRNA levels of P and FasL genes were found to be significantly lower for patients with type 1 diabetes compared to normal controls (p < 0.05). However, there was no significant difference for GB mRNA levels between patients and controls (p > 0.05). The decreased expression of P and FasL in patients with long-term type 1 diabetes might contribute to the inability to maintain normal levels of peripheral tolerance, which is essential for protection from autoimmune disease.