The aim of this study was to evaluate the mixture of Calcium Sulfate and Plasma Rich in Growth Factors (CaSO4 + PRGF) as a bone-graft substitute in extracted mandibular third molar (MTM) alveoli during a 4-month period. Bilateral MTM extractions were performed in 10 patients (18–25 years) at the Oral-Surgery-Clinic of the Universidad Autónoma de Yucatán (UADY). A CaSO4 + PRGF mixture was placed in the right alveolus (Experimental Group (EG)) and a natural blood clot in the left (Control Group (CG)). Monthly X-ray controls were performed using a gray scale to measure Bone Regeneration (BR). A non-parametric Sign Test was used to evaluate Radiopacity/Bone Regeneration (Ro/BR) over 4 months, and a Friedman’s non-parametric test was used for intra-group analysis over these months. The study was approved by the Centro de Investigaciones Regionales (Dr. Hideyo Noguchi, UADY Bioethics Committee, ID 0026-2015). Using a non-parametric test of the sign, the EG showed significant difference of Ro/BR between groups p = 0.002 (p < 0.05). Significant differences were observed in all quadrants and areas p = 0.002 (p < 0.05) except in area A in month 4 (p = 0.016), which could be explained by its being the closest to native bone. EG CaSO4 + PRGF showed a higher degree of bone regeneration compared to CG.