AbstractBackground One of the major complications associated with random-pattern skin flaps is distal necrosis. Cannabidiol (CBD) has recently gained much attention as a therapeutic anti-inflammatory agent. We aimed to evaluate the efficacy of CBD on the random-pattern skin flap survival (SFS) in rats and to explore the possible involvement of cannabinoid type-2 (CB2) receptors.Methods In this controlled experimental study, we randomly divided male Wistar rats into seven study groups (six rats each). We performed a random-pattern skin flap model in each rat following pretreatment with vehicle (control) or multiple doses of CBD (0.3, 1, 5, or 10 mg/kg). In a separate group, we injected SR144528 (2 mg/kg), a high affinity and selective CB2 inverse agonist, before the most effective dose of CBD (1 mg/kg). A sham nontreated and nonoperated group was also included. Seven days after surgeries, the percentage of necrotic area (PNA) was calculated. Histopathological microscopy, CB2 expression level, and interleukin (IL)-1β and tumor necrosis factor (TNF)-α concentrations were also investigated in the flap tissue samples.Results A PNA of 72.7 ± 7.5 (95% confidence interval [CI]: 64.8–80.6) was captured in the control group. Following treatment with CBD 0.3, 1, 5, and 10 mg/kg, a dose-dependent effect was observed with PNAs of 51.0 ± 10.0 (95% CI: 40.5–61.5; p <0.05), 15.4 ± 5.8 (95% CI: 9.3–21.5; p <0.001), 37.1 ± 10.2 (95% CI: 26.3–47.8; p <0.001), and 46.4 ± 14.0 (95% CI: 31.7–61.1; p <0.001), respectively. Histopathologically, tissues enhanced significantly. Besides, CB2 expression surged remarkably, IL-1β and TNF-α concentrations decreased considerably after treatment with CBD of 1 mg/kg compared with the control (p <0.05 and <0.001, respectively). Administering SR144528 reversed the favorable effects of CBD of 1 mg/kg, both macroscopically and microscopically.Conclusion Pretreatment with CBD of 1 mg/kg improved SFS considerably in rats and exerted desirable anti-inflammatory effects which were possibly mediated by CB2 receptors.