Hydroxypropylmethylcellulose (HPMC)-based solid dispersions (SDs) and physical mixtures (PMs) were prepared to enhance the dissolution rate of poorly water-soluble drugs. The roles of the acidifiers on structural crystallinity and drug dissolution rate were investigated. A poorly water-soluble drug, raloxifene HCl (RXH), was used as the model drug. The SDs and PMs were prepared with HPMC, drugs, and acidifiers using the spray-drying method and then compressed into tablets. The dissolution rate of RXH from SDs was ranked by acidifiers in increasing order: glycolic acid, citric acid, and fumaric acid. On the other hand, the acidifiers in PMs did not significantly affect the drug dissolution rate. Scanning electron microscopy was used to analyze the surface morphology of the SD and PM samples. Differential scanning calorimetry and X-ray diffraction were used to analyze the SD crystallinity. Fourier-transform infrared spectroscopy was used to analyze the characteristic changes of the SD chemical structure. The in vitro release behavior of SDs and PMs was examined in simulated gastric fluid. The dissolution rate of RXH from SDs and PMs was higher than that of the pure drug. The dissolution rate of RXH from SDs was higher than that of PMs and original RXH due to the decreased particle size and hydrogen bond between the drug and the carrier.