Raman spectroscopy is developed as a fast and non-destructive method for the discrimination and classification of hydroxypropyl methyl cellulose (HPMC) samples. 44 E series and 41 K series of HPMC samples are measured by a self-developed portable Raman spectrometer (Hx-Raman) which is excited by a 785 nm diode laser and the spectrum range is 200–2700 cm−1 with a resolution (FWHM) of 6 cm−1. Multivariate analysis is applied for discrimination of E series from K series. By methods of principal components analysis (PCA) and Fisher discriminant analysis (FDA), a discrimination result with sensitivity of 90.91% and specificity of 95.12% is achieved. The corresponding receiver operating characteristic (ROC) is 0.99, indicting the accuracy of the predictive model. This result demonstrates the prospect of portable Raman spectrometer for rapid, non-destructive classification and discrimination of E series and K series samples of HPMC.