Objectives <p>To evaluate cases of persistent apical periodontitis (PAP) and what are the imaging and clinical aspects that could be considered in the PAP diagnosis and in their treatment decision-making process.</p> Methodology <p>423 patients with apical periodontitis at the time of non-surgical root canal treatment (NSRCT) were followed-up for at least 1 year. Periapical radiographic images were used to compare and determine periapical status at each time using the PAI scoring system. Cases scored as PAI 5 at the follow-up appointment were evaluated by CBCT, using the CBCTPAI scoring system. Associated, the data from imaging exams and from clinical evaluation were considered to make a decision for PAP treatment.</p> Results <p>Regarding sample composition, it was observed an association with ethnicity and PAP (<i>p</i> = 0.045). After follow-up, cases classified as PAI Score 1 and 2 and absence of symptoms/complaint were classified as successful. Cases classified as PAI Score 3 and absence of symptoms/complaint were referred for new follow-up visits until complete resolution of PAP. Cases scored as PAI 4 with clinical symptoms were indicated for non-surgical root canal retreatment. Cases scored as PAI 5 were assessed by CBCT, and in the presence of symptoms/complaint and a CBCTPAI score 3 were related to non-surgical root canal retreatment, while CBCTPAI scores 4 and 5 were refereed for endodontic surgery.</p> Conclusions <p>Clinical data, PAI and CBCTPAI scoring systems from image exams can be useful for PAP diagnosis and their treatment.</p> Clinical relevance <p>In the decision-making process, clinical and imaging data are fundamental for the choose of an ideal protocol for treating PAP.</p>