Peri-implant disease has developed over the last few years as a complication that is often difficult to resolve. The disease process is mainly attributed to bacterial infection. Proposed combined therapies use broad-spectrum antibiotics to halt its progression. A major associated risk is the undetected development of superinfections that are difficult to eradicate. A group of healthy individuals with advanced peri-implantitis (PI) were referred for evaluation due to severe, rapidly progressive bone loss. Previous nonsurgical and empiric antibiotic therapy had been rendered. Culture and polymerase chain reaction-based identification were performed for PI lesions, healthy implants, and saliva. Clinical and radiographic examinations revealed peri-implant bleeding on probing, deep pockets, and severe radiographic bone loss with absence of lamina dura. A number of superinfecting agents were identified, such as Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Candida albicans, and Epstein-Barr virus (EBV). EBV is significantly more prevalent at peri-implantitis sites than at healthy implants and in saliva. Specific systemic antimicrobial therapy and nonsurgical or surgical debridement may eradicate some opportunistic pathogens, but follow-up tests should be performed to identify potential emerging pathogenic microbiota, such as C albicans and enteric rods, at peri-implant sites. Antifungal and antiviral therapy may be needed. Due to the extent and severity of tissue loss, some implants were removed. Peri-implant superinfections are a major risk associated with broad-spectrum antibiotics in immunocompetent individuals. Lack of follow-up and antibiotic susceptibility testing and indiscriminate empiric treatment regimens may lead to ongoing microbial challenge that exacerbates and maintains the disease progression. Personalized periodontal supportive therapy could prevent risks by sustaining a healthy microbial ecologic balance, reducing specific pathogen proportions, maintaining optimal plaque control, and detecting early signs of inflammation.