Increasing the 1,3,5-trioxane (TOX) concentration in the equilibrated vapor phase of TOX–H2O system has been recognized as a challenge for the azeotrope. Ionic liquids (ILs) were used to improve the relative volatility of TOX to H2O and destroy the azeotrope in the TOX–H2O system. The vapor–liquid equilibrium of TOX–H2O system at 101.3 kPa was studied with the addition of 1-butyl-3-methylimidazolium hydrogen sulfate, 1-hexyl-3-methylimidazolium hydrogen sulfate and 1-butyl-3-methylimidazolium nitrate, respectively. The results showed that the volatility of TOX increased with the increase in IL dosage. And the volatility of water decreased with the increase in IL dosage. The relative volatility of TOX to H2O was improved with the increase in ILs dosage. The azeotrope could be destroyed with an IL mole fraction of about 0.10. A non-random two-liquid (NRTL) model was successfully used to correlate the experimental data. The interaction parameters were obtained by fitting the experimental data with the model. The results indicated that a strong interaction existed between ILs and water. The strong interaction improved the volatility of TOX and inhibited the volatility of water, and then intensified the relative volatility of TOX to H2O. The results showed that an ILs with strong polarity and hydrophilicity may be a potential additive to improve the TOX concentration in the equilibrated vapor phase.