Objective To analyze the prevalence of distal caries in mandibular second molars (M2Ms) and its correlation with the threedimensional position of mandibular third molars (M3Ms) by cone beam computed tomography (CBCT) images. Materials and methods CBCT scans involving 421 M3Ms were assessed. The presence of distal caries of M2Ms, patient age and gender, impaction depths and mesial angulation of M3Ms, the cementoenamel junction (CEJ) distances and contact point localization, and the horizontal positions of M3Ms were assessed. Risk factors were identified by multivariate logistic regression analysis. Results The overall prevalence of distal caries in M2Ms was 31.6%. Mesial angulation (16°-75°) of M3Ms, contact point localization at or below the CEJ of M2Ms, and a buccal or lingual position of M3Ms relative to the molar line were identified as risk factors for the prevalence of distal caries in M2Ms (p < 0.05). Distal caries was more severe when the mesial angulation of M3Ms was 16°-75°(p < 0.05). Conclusions Buccal or lingual position of M3Ms may represent a new risk factor for the distal caries in M2Ms. Mesial angulation (16°-75°) of M3Ms is a predictive parameter for both the presence and severity of distal caries in M2Ms. Clinical relevance As the presence of distal caries in M2Ms is significantly associated with the three-dimensional position of M3Ms, watchful monitoring or prophylactic removal of M3Ms should be deliberated when M3Ms are mesially angulated (16°-75°), buccally or lingually positioned, and with the contact point localization at or below the CEJ of M2Ms.