A gas-phase derivatization strategy is reported by using the gas-phase Meerwein reaction for rapid and direct LC–MS analysis of epoxides, which are potential genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs). This class-selective ion/molecule reaction occurs between epoxides and the ethylnitrilium ion Symbol that is generated by atmospheric pressure ionizations (when acetonitrile is used as the mobile phase). Density functional theory (DFT) calculations at the B3LYP/6-311+G(d,p) level show that the gas-phase Meerwein reaction is thermodynamically favorable. Commonly used atmospheric pressure ionization techniques including ESI, APCI and APPI were evaluated for optimal formation of the Meerwein reaction products. APCI appears to be the method of choice since it offers better sensitivity and more robust detection under typical LC–MS instrumentation conditions. Quantitative analysis of epoxides can be achieved by either single ion monitoring (SIM) or multiple reaction monitoring (MRM) of the Meerwein reaction products. We demonstrate herein quantitative analysis of two potential GTIs of SB797313 and SB719133 in APIs. The validated methods afford excellent linearity (r2 ≥ 0.999), sensitivity (LOD ≤ 1 ppm by w/w in 10 mg/mL APIs) and recovery (ranging from 92% to 102%), as well as accuracy (≤2.8% difference) and precision (≤2.2% RSD) based on injections of six prepared standards. This novel strategy is particularly useful when a target analyte is difficult to be directly analyzed by LC–MS (e.g. due to poor ionization) or unstable in the course of solution-phase derivatization.