Background: Today, there are several diagnostic methods to determine the exact size and nature of periapical lesions. Furthermore, there are studies that described thickening of the mucous membrane of the maxillary sinus (MS) in patients with periapical lesions and demonstrated a causal relation. Aims: This study aims to evaluate the morphological variations of the MS floor (MSF) adjacent to chronic periapical lesions in molars and premolars using cone-beam computed tomography (CBCT). Methods: Twenty-five CBCTs with periapical lesions adjacent to maxillary molars and premolars were evaluated. A total of 50 maxillary sinuses were analyzed (12 males and 13 women) taking into account density changes within the sinus cavity. The thickening of the sinus mucosa and the periapical lesions was measured in a caudal-cephalic direction. The axial and sagittal axis was taken as reference on the sagittal and coronal sections. Statistical Analysis: Chi-square, Fisher exact, and the Mann-Whitney tests were used in this study. Results: A significant association between the size of the periapical lesions (>4 mm) and the presence of MSF affectation was found on sagittal and coronal views (P < 0.001). No significant differences between the presence or absence of periapical lesions and the thickening of the sinus mucosa were found (P = 0.241). The presence of opacification on the MS had no direct associations with the periapical lesions. Conclusions: Maxillary sinus floor affectation was associated with chronic periapical lesions >4 mm. The opacification or thickening of the sinus mucosa was not related with the periapical lesions.