Endodontic and periodontal tissues exhibit a significant interrelationship, whereby pathologies affecting one tissue can precipitate the involvement of the other. The primary objective of this study was to assess the risk factors associated with endo-perio lesions (EPLs). The secondary objective was to assess the prognostic predictors for such lesions and the prevalence rate of EPLs involving both pulpal and periodontal tissues in Indian cohorts. A prospective observational study was conducted on 2170 teeth with EPLs in Indian adults aged > 18 years. A detailed history of smoking, tobacco chewing, and the development of EPLs was obtained from all patients. Detailed periodontal and endodontic examinations were conducted by two calibrated examiners. Intraoral periapical radiographs (IOPAs) were obtained to diagnose EPLs. The chi-square test of association was used to analyze the association between independent and dependent variables, and the strength of association was presented by Pearsoncontingency coefficient (r). Logistic regression analysis was performed to identify reliable factors for diagnosing EPLs. A statistical significance threshold of 0.05 was established. The prevalence of EPLs involving pulpal and periodontal tissues was 29.49%. Type 1 lesions (EPLs involving only pulpal tissue) were most commonly seen at 41-45 years of age, type 2 lesions (EPLs involving primary pulpal and secondary periodontal tissue), and type 3 lesions (EPLs involving only periodontal tissue) at 26-30 years of age, and type 4 lesions (EPLs involving primary periodontal and secondary pulpal tissue) at 31-35 years of age. The pulp was found to be non-vital in all cases of type 3 lesions, and faulty restoration or improper root canal treatment (RCT) was the main risk factor for such lesions. Occupational trauma was found to be the most common risk factor for type 3 and type 4 lesions. Smoking, age, tooth type, occlusal trauma, faulty restorations and RCT, presence of caries, periapical pathology, periodontitis, bone loss, and pulp vitality were significantly associated with EPLs. Pulp vitality and bone loss were two prognostic predictors of EPLs.