Objectives: Severe burn injuries represent a significant public health risk and are often associated with a life-threatening systemic inflammatory response. With the traditional approach, patients often have a prolonged hospital stay and are more prone to develop problems like joint contractures, hypertrophic scars and infection, due to the delayed wound healing process. Although many parameters of the immune system are depressed or altered, only the innate immune system has been directly correlated with infections in these patients. The innate immune system plays an important role in both the inflammatory response and defense against infections. In this study, we report a critical requirement for NKT and regulatory T cells (Tregs), as well as the role of cytolitic molecule perforin in the immune dysfunction that occurs early after burn injuries. Patients and methods: Human peripheral blood mononuclear cells (PBMNC) from healthy adult volunteers and from patients with severe burn injuries were taken and phenotype of lymphocytes and perforin expression were analyzed using intracellular and surface immunofluoresecncy and flow cytometric analysis (FACSCalibur). Simultaneously, with the phenotype of lymphatic cells determined by FACS staining, the spontaneous cytotoxic activity of freshly isolated MNLC was measured against NK-sensitive target. Statistical analysis was done in computer program Statistica 7.1 (StatSoft, Inc., Tulsa, OK, USA). Graphs and tables were done in computer program Microsoft Excel. Results: Our findings indicate that the percentage of double staining CD3/CD4 and CD3/CD8 and positive cells are significantly decreased in peripheral blood of burned patients, while the percentage of NKT and Treg cells has shown significant augmentation. During the therapy diminished value were slowly normalizing, while the average of NKT and Treg cells were higher, indicating the role of these “primitive” lymphocytes in control of innate immunity. Our data also demonstrated that only 10-15% of PBL in patients are perforin positive (total perforin of burned patients are 40% lower than in control group). Percentage of all double positive cells showed significant decrease (CD3+ P+, CD4+P+, CD8+P+, CD16+P+, CD56+P+) in patients with burns injuries in comparation with healthy volunteers, showing the possible prognostic recovery value of these findings. Cytotoxic activity of PBMNC of burned patients was significally lower than in control group. Conclusion: Our results suggest that human perforin is differentially expressed in distinct subpopulations of peripheral blood lymphocytes of our patients, indicating the important role of perforin positive cells in naïve immune response and cytotoxic activity of peripheral blood cells of patients with burn injuries. The immunoregulatory functions of NKT and Treg cells in burn injuries are marked and we are able to discuss NKT and Treg cell-based immunotherapeutic strategies.