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The aim of this study was to examine the expression of organic cation transporter 3 (OCT3) in patients with oral submucous fibrosis (OSF)–associated buccal squamous cell carcinoma (BSCC) and to explore its clinical significance.A total of 56 tissue specimens were collected from patients, among which there were 13 specimens with normal buccal mucosa (NBM), 13 with oral submucous fibrosis (OSF), 10 with OSF-associated BSCC (BSCC-OSF), 10 with well-differentiated BSCC (BSCC-I), and 10 with poorly to moderately differentiated BSCC (BSCC-II+III), based on pathologic examination. The expression of OCT3 was detected by using immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction.There was a significant difference in both the protein and mRNA expression levels of OCT3 among the NBM, OSF, BSCC-OSF, BSCC-I, and BSCC-II+III groups (protein: F = 82.45 [P < .0001]; mRNA: F = 50.69 [P < .0001]). The expression of OCT3 from NBM to OSF to BSCC-OSF was gradually upregulated. In addition, as BSCC became better differentiated, the expression of OCT3 increased.The expression of OCT3 was associated with OSF progression and the differentiation of BSCC. OCT3 expression may serve as a molecular marker for the prevention and early diagnosis of OSF and BSCC.