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INTRODUCTION. Endodontic-periodontal combined lesions are complicated clinical cases with prognoses that vary in their predictability with regard to the underlying etiology and involvement. The interdependence between lesion classification and outcome of treatment is yet to be fully defined. MATERIALS AND METHODS. 165 teeth with endodontic-periodontal lesions were used in a prospective cohort study (Group A primary endodontic lesions with secondary periodontal involvement, n = 55), Group B primary periodontal lesions with secondary endodontic involvement, n = 55) and Group C true combined lesions, n = 55). Every tooth was subjected to the right endodontic and periodontal treatment. Clinical outcomes such as probing pocket depth (PPD), clinical attachment level (CAL), tooth mobility, as well as periapical index after 3, 6, 12 months were evaluated. Success with the treatment, survival of the teeth, and patient-reported outcomes were assessed. RESULTS. The general success rate of treatment was 73.3 and the differences between the groups were significant: Group A (89.1%), Group B (69.1%), Group C (61.8%), p <0.001. Groups A showed better results with 4.82 plus or minus 1.24 mm difference in mean PPD reduction compared to 3.41 plus or minus 1.38 mm difference in Group B and 2.87 plus or minus 1.52 mm difference in Group C at the age of 12 months ( p < 0.001). Group A, Group B and Group C showed a mean CAL gain of 4.15 + 1.18 mm, 2.94 + 1.32 mm and 2.31 + 1.45 mm respectively ( p < 0.001). The tooth survival rates in Group A (94.5), Group B (83.6), and Group C (76.4) were significant ( p = 0.012). Patients with initial PPD > 7 mm (OR = 3.84, p < 0.001) and true combined lesions (OR = 4.92, p < 0.001) were important predictors of treatment failure. CONCLUSIONS. Primary endodontic lesions through secondary periodontal involvement portray highly better treatment results than primary periodontal lesions or true combined lesions. Lesion classification is a vital prognostic factor, which is used in the treatment planning and counseling of patients.