This study aimed to assess the differential clinical response to step 2 of periodontal therapy and repeated subgingival instrumentation between teeth with suprabony and intrabony defects. Electronic and manual searches were performed to identify studies reporting the differential clinical outcomes of nonsurgical periodontal therapy (NSPT) in the presence or absence of intrabony defects. The Cochrane Risk of Bias 2 and the Newcastle-Ottawa scale were used to assess the risk of bias. A total of 2,348 articles were initially screened, and a total of 5 articles were finally included. Regarding the primary outcome measure, two studies reported probing pocket depth (PPD) reductions at 6 months after step 2 of periodontal therapy, showing an opposite response of intrabony defects compared to suprabony defects (3.2 ± 1.9 mm intrabony vs 2.2 ± 1.7 mm suprabony in one study, and 0.48 ± 0.42 mm intrabony vs 0.72 ± 0.36 mm suprabony in the other), while one study reported no differences at 3 months. One study showed a negative association between the presence of an intrabony defect and PPD reduction at 9 months after nonsurgical step 3 (P < .05). Due to the limited number of studies and heterogeneity of the data, conflicting evidence emerged for the differential response to NSPT of intrabony and suprabony defects.