Quantum dots (QDs) are a new class of fluorescent probes to detect biomarker expression. The role of caveolin-1 (Cav-1) in tongue squamous cell carcinoma (TSCC) is still unknown. This study aimed to investigate the expression profile of Cav-1 in carcinogenesis and development of TSCC by QDs immunofluorescence histochemistry (QDs-IHC) and discuss the relationship between the Cav-1 expression and the clinicopathological outcomes. QDs-IHC was used to detect Cav-1 expression in tissue microarrays including normal tongue mucosa (NTM; n=10), hyperplastic tongue mucosa (HTM; n=10), tongue pre-cancer lesions (TPL; n=15) and primary tongue squamous cell carcinoma (PTSCC; n=61). Correlations between the Cav-1 expression and clinicopathologic variables were evaluated statistically. Cells positive for Cav-1 were clearly detected and bright images were obtained in a fine, granular pattern at the cell membrane and cytoplasm using QDs-IHC. The rate of Cav-1 immunoreactivity increased progressively from NTM (0%), HTM (0%), TPL (36%) to PTSCC (74%). When compared with each other, there was statistical significance among PTSCC, TPL and NTM as well as among PTSCC, TPL and HTM. Moreover, Cav-1 expression level in PTSCC was correlated positively with clinical stage and histologic grade. QDs-IHC could accurately detect protein location in tongue mucosa. An increased expression of Cav-1 in the stepwise carcinogenesis from NTM, HTM, TPL to PTSCC suggested that Cav-1 might be an oncogene in the development of tongue squamous cell carcinoma.