OBJECTIVES: LTF SNP rs1126478 (T>C) could modulate Lactoferrin function and release and has been associated with periodontal disease in different locations before, but not in America. Thus, this study aimed to assess the association between this SNP and Grade C Periodontitis (Generalized (PerioC-G) and Molar Incisor Pattern (PerioC-MIP)) and seek a relationship between its presence and LTF gingival crevicular fluid (GCF) production. MATERIAL AND METHODS: Oral cells from 361 Brazilians and 375 North Americans patients (Diseased and Health Controls (PH) from both locations) were collected. DNA was extracted, and a prefabricated probe system determined rs116478 genotyping. Immunoenzymatic analysis detected LTF levels in GCF. RESULTS: Higher allelic altered-C frequency was associated with PerioC. For PerioC-G, CT and CC genotypes presented a frequency of 44.7% and 34.1%, respectively, while 37.3% and 26.4% were found to PH group (OD=2.1 (p=0.004) for CT and OD=2.3 (p=0.003) for CC). PerioC-G was associated with a lower concentration (742.2±717.9 pg/ml) of LTF than PerioC-MIP (5851±5859.2 pg/ml), p<0.0001. Multiple logistic regression showed that CC genotype impacted LTF levels by acting as a predictor (β =2.457, p=0.02, OD=1.17) despite the site or diagnosis. CONCLUSION: There is an association of rs1126478 with Grade C periodontitis, mainly the PerioC-G. Lower LTF levels in GCF might be associated with the generalized disease pattern. CLINICAL RELEVANCE: This study assessed and compared the genetic background in two distinct locations, paving the way for new studies regarding personalized risk and treatment for different ethnicities. As this SNP is in a region related to the antimicrobial function of LTF, it could impact PerioC-MIP and PerioC-G response against periodontopathogens. This discovery opens the way for in vitro studies analyzing the functionality of this SNP, and, in the future, it can be used to treat PerioC, individualizing the phenotypes.