Background: Irisin and adipomyokine are proteins secreted by the body during exercise and exhibit potential therapeutic effects for chronic disorders. Gaining insights into how high-intensity resistance training and endurance training influence irisin and adipomyokine secretion could shed light on optimizing exercise regimens for potential therapeutic applications. Such knowledge could pave the way for personalized exercise prescriptions and contribute to the development of novel treatments for chronic conditions, enhancing overall health and well-being.Objectives: To investigate the effects of high-intensity resistance training (HIRT) and endurance training on irisin and adipomyokine levels in healthy individuals.Methods: An 8-week interventional comparative study was conducted at Nimra Institute of Medical Sciences, Andhra Pradesh, India. One hundred healthy male individuals aged 21 to 35 were divided into two groups: HIRT and endurance. The HIRT group performed high-intensity resistance training, while the endurance group performed endurance training. Ethical approval was obtained, and baseline and post intervention values of the participants were recorded and analyzed using SPSS software.Results: After 8 weeks, irisin levels were significantly elevated in the HIRT group (167.39 +/- 11.27) compared to the endurance group (155.39 +/- 11.28). A positive correlation was observed between skeletal muscle and irisin levels in both the HIRT group (chi 2-16.38; p=0.04) and the endurance group (chi 2-18.36; p=0.01). Additionally, TNF-alpha (HIRT: 81.47 +/- 4.02 and Endurance: 61.19 +/- 4.00) and interleukin-6 (IL-6) (HIRT: 46.84 +/- 4.46 and Endurance: 36.15 +/- 3.89) levels significantly increased in the HIRT group. However, there was no significant change in leptin levels in either group (HIRT: 3.75 +/- 0.58 0.58 and 4.15 +/- 0.58).Conclusion: The findings of this study indicate that HIRT is more effective in increasing irisin levels compared to endurance training. However, the notable elevation of IL-6 and TNF-alpha in the HIRT group raises concerns about potential chronic inflammation. To optimize outcomes, a combined approach, coupling HIRT and endurance training, may be beneficial. Additionally, the results emphasize the significance of skeletal muscle as a primary source of irisin secretion, implying that increased muscle contraction contributes to higher irisin release even in healthy individuals. These insights can guide exercise prescriptions and potentially enhance therapeutic strategies for chronic disorders.