Antiviral drugs are widely used for human and animals. However, the analysis of the mixture of antiviral drugs is a challenge for high performance liquid chromatography, since some of the antiviral drugs have weak UV absorbance and poor retention in reversed phase liq- uid chromatography. A method of hydrophilic interaction liquid chromatography-charged aerosol detection (HILIC-CAD) was optimized for the qualitative and quantitative analysis of five antiviral drugs. In this study, Click TE-Cys was used as the stationary phase and CAD was used as the detector. Various chromatographic conditions including the kind of detector, chromatographic mode, column and mobile phase composition were investigated. Compared to UV-Vis, more antiviral drugs could be detected by CAD, since it is a universal detector. HILIC mode is an alternative to reversed phase liquid chromatography mode. HILIC provides higher sensitivity and unique selectivity to target compounds. After the optimized parameters were obtained, the developed method was used for the quantitative analysis of the five antiviral drugs. As a result, the current method has good repeatability, a wide linear range (0.07-2.28 mg/mL) and good sensitivity (LOQ ≤ 0.04 mg/mL). The RSDs of intra-day and inter-day peak areas were less than 3. 06% and 5. 38% respectively. The above results demonstrated that the current method is sensitive, robust and effective for the separation and determination of these five antiviral drugs.