Objectives: Perforin and granzyme B are essential proteins for protective immune responses mediated by Cytotoxic T Lymphocytes (CTLs) and Natural Killer cells (NK) against cancers, especially those of hematological origin. Our study investigated polymorphisms in the perforin gene (PRF1) and quantified the levels of the perforin and granzyme B proteins in patients with multiple myeloma (MM). Methods: The PRF1 coding region was evaluated in 58 patients with MM and 78 healthy individuals using direct sequencing. Quantitative real-time PCR was performed to quantify gene expression, and flow cytometry was used to determine the intracellular protein levels. Results: We did not observe differences in the allele frequencies of polymorphisms in the PRF1 gene as well as in perforin and granzyme B protein expression between patients with MM and healthy individuals. However, reduced expression of perforin or granzyme B genes was associated with a shorter survival time. In addition, patients with MM had significantly more CTLs expressing perforin and granzyme B, and had an increased number of NK cells. Conclusion: Our study suggests that the gene expression profile of perforin and granzyme B is a potential prognostic marker for MM.