Background and Objective. The injuries caused by reperfusion of blood can lead to significant adverse effects after surgery. This study aimed to compare the effects of spinal and general anesthesia on inflammatory cytokines following changes in ischemic reperfusion due to tourniquet in lower limb surgeries. Methods. In this randomized controlled clinical trial, 34 patients with lower limb surgery admitted at the orthopedic ward of Imam Reza Hospital, Birjand, Iran, were selected by the available sampling method. They were randomly divided into two groups as follows: general anesthesia (n = 17) and spinal anesthesia (n = 17). Venous blood samples were taken from the patients of both groups at baseline (before the use of tourniquet) and 12 and 24 hours after reperfusion. Interleukin-6 (IL-6), tumor necrotizing factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), and ferritin were measured and recorded. The data were analyzed using independent t-test, chi-square, and repeated measure at the significant level of 0.05. Results. The results showed that hs-CRP and IL-6 significantly increased during the study (
p
<
0.001
); however, the mean changes of TNF-α and ferritin were not significant during the study. Moreover, none of the inflammatory cytokines indicated significant differences between these two study groups (
p
<
0.05
). Conclusion. According to the results, the use of tourniquet can lead to inflammation, and the inflammation is similar in both groups.