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Objective The present study was designed to investigate (1) whether the non-human primate would be an appropriate animal model for the study of spontaneous periodontitis and its association with metabolic syndrome (MetS), and (2) whether microRNAs (miRNAs) play roles in the co-development of metabolic disorders and periodontitis. Design Rhesus monkeys (aged 12–29 years) with or without MetS were analyzed for the prevalence of periodontitis. The potential mechanisms underlying the association between MetS and periodontitis were explored using miRNA profiling of the gingival tissues from the MetS monkey groups with or without periodontitis as well as the age-matched controls. Results Among the 57 rhesus monkeys examined, 18 were diagnosed with periodontitis according to the inclusion criteria, with an overall prevalence of 31.6%. Moreover, the prevalence of periodontitis was 8.3% in the control group, 18.2% in the at-risk group, and 44.1% in the MetS group. The C-reactive protein level was doubled in the MetS periodontitis group, compared to the non-periodontitis sub-groups. Most importantly, only 3 miRNAs were confirmed to be differentially expressed between the MetS periodontitis and non-periodontitis subgroups while other miRNAs showed similar expression profiles. Conclusions The results indicate that the monkey with MetS is an ideal model for studies of spontaneous periodontitis and its association with MetS. miRNA profiling using this unique model showed that miRNAs play roles in the co-development of MetS and periodontitis.