Objective: To test the effectiveness of nonsurgical and surgical treatment methods for clinical and radiographic peri-implantitis symptoms resolution with respect to pocket probing depth (PD), bleeding on probing (BOP), and marginal bone-loss reduction (RBL); to propose guidelines for managing peri-implantitis. Method and Materials: An electronic literature search was conducted of the MEDLINE and EMBASE databases for articles published between 2002 and 2015. Sequential screening at the title/abstract and full-text levels was performed. Clinical human studies in the English language that had reported changes in PD and/or BOP and/or radiologic marginal bone level (RBL) changes after peri-implantitis treatment at 6-month follow-up or longer were included. A meta-analysis was performed using the random-effects model on the selected qualifying articles. Results: The search resulted in 29 articles meeting the inclusion criteria. The meta-analysis demonstrated improved BOP values (P = .001; OR = 1.567; 95% CI, 1.405 to 1.748) after the nonsurgical treatment but did not reveal a statistically significant difference in the PD changes (P = .8093; standardized mean difference [SMD] = 0.346 mm; 95% CI, 0.181 to 0.512). There was a significant improvement in PD (P .001; SMD = 1.647 mm; 95% CI, 1.414 to 1.880) and BOP values (P .001; OR = 4.044; 95% CI, 3.571 to 4.381) after surgical treatment and an intrabony defect fill was found to be 1.66 mm (1.0) using a regenerative treatment modality. Our meta-analysis confirms there is a significant reduction in RBL after nonsurgical (P = 0.037; SMD = 0.157 mm; 95% CI, −0.183 to 0.496), resective (P = .0212; SMD = −0.116 mm; 95% CI, −0.433 to 0.201), and regenerative (P = .0305; SMD = 1.703 mm; 95% CI, 1.266 to 2.139) surgical treatment. A novel complex management and maintenance (CMM) six-step protocol is thus suggested for treatment of peri-implantitis. Conclusion: Regenerative surgical treatment of peri-implantitis was found to be most effective. A novel six-step protocol aimed at managing patients with peri-implantitis can be a useful tool in peri-implantitis treatment. Keywords: peri-implantitis, review, treatment, therapy