Background: Microparticles are generated in vivo with exposures to high pressure gases by unclear mechanisms. Results: High inert gas pressure causes singlet oxygen formation, which initiates a cycle of actin S-nitrosylation, nitric-oxide synthase-2, and NADPH oxidase activation leading to microparticle formation. Conclusion: Inert gas-mediated oxidative stress causes microparticle production. Significance: This mechanism may initiate events leading to decompression sickness.