Conselho Nacional de Desenvolvimento Científico e Tecnológico Desenvolvimento (CNPq). Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).Introduction/Objective. STAT3 (signal transducers and activators of transcription) is involved in different physiological processes, including cell proliferation and survival. High expression of this protein is observed in various types of cancer. This study aimed to investigate the gene and protein expression of STAT3 in a series of odontogenic cysts and tumors to provide more information about their biological profile. Methods. The STAT3 gene expression at mRNA was quantified by real-time quantitative polymerase chain reaction (RT-qPCR) in 23 odontogenic keratocysts (OKCs) and 7 ameloblastomas (AMs), and compared to the non-neoplastic oral mucosa. We also assessed the expression of STAT3 gene at protein levels, using immunohistochemistry, in 43 OKCs and 47 AMs. Results. STAT3 transcripts were found in 96.6% of the tumors studied; however, the gene was downregulated in OKC and AM compared to the non-neoplastic oral mucosa. The STAT3 gene expression at mRNA level was higher in sporadic OKC than syndromic OKC (p = 0.04). There was no difference in STAT3 gene expression at mRNA level between OKCs and AMs (p = 0.88). Immunostaining of STAT3 revealed no significant difference between sporadic and syndrome OKC (p > 0.05), nor between conventional and unicystic AMs (p > 0.05). Ameloblastomas exhibited significantly higher STAT3 immunostaining than OKCs (p = 0.03). In OKC and AM, STAT3 immunostaining was predominantly cytoplasmic and no difference in the cellular localization of STAT3 was observed between these lesions (p = 0.58). Conclusion. Our findings showed low expression of STAT3 gene in OKCs and AMs in relation to non-neoplastic oral mucosa. However, higher STAT3 immunostaining was observed in AMs compared to OKCs.