Qinghaosu and derivatives were easily reduced by ferrous sulfate in aqueous acetonitrile to give results different from those reported for other reducing systems. The unstable epoxide 7, a compound that was postulated earlier as a species responsible for the antimalarial activity, now has been isolated and characterized. The earlier speculative secondary C-4 radical has also been trapped with 2-methyl-2-nitrosopropane and thus provides the very first direct evidence for the involvement of radicals in the in vitro cleavage of QHS-type compounds. A unified mechanism featuring interchangeable radical anions and reversible intramolecular radical reactions is proposed for the ferrous ion induced cleavage of the 1,2,4-trioxanes (i.e., QHS and the like). On the basis of this framework, together with consideration of counterion and solvent effects, a large body of divergent experimental outcomes can be satisfactorily rationalized, not only the formation of the main products but also the product ratios as well as their deviation from those obtained under other reaction conditions.