Background: Sometimes dental implants seem to be the only therapeutic alternative for the oral rehabilitation of patients with Down syndrome, given that they usually lose all their teeth early due to suffering aggressive periodontitis and they do not usually have the skills required to wear removable prostheses. However, the evolution of dental implants in these patients shows very adverse results. It is possible that basal genetic alterations, or at least some characteristics of these, may underlie these clinical results. The metabolic pathway of metallothioneins, molecules with an important influence on bone metabolism, could be one of the said alterations. Aims: To determine whether the expression of metallothioneins (MTs) and their metabolic pathway may be identified and related to the periodontitis and lack of osseointegration of dental implants in Down syndrome patients. Materials and Methods: Retrospective study of cases and controls by comparing patients with Down syndrome, periodontal disease, and implant failure (four patients, test group) with patients with Down syndrome, without periodontal disease, and without implant failure after two years of following (seven patients, control group), by extracting peripheral blood at the time of the dental examination to extract RNA and its subsequent processing in relation to gene expression of the metabolic pathway of metallothioneins. Results: The results identified low expression in the group of patients with periodontal disease and implant failure of genes MT1E, MT1H, MT1X, MT1A, MT1B, MT1C, MT1L, MT2A, MT1M, and MT1G. Conclusions: The low MT1 and MT2 gene expression seems to be related to the onset of periodontal disease and implant rejection in Down syndrome patients, although more data are required to confirm whether this relationship is due to one of the two conditions, to both independently, or to the two jointly—this last option being indicated by our current study.