Background: Tumor cells adapt to hypoxia by regulating transcription factors that involved in regulation of metabolism, angiogenesis, cell proliferation, and apoptosis. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1 alpha and HIF-1 beta subunits, acts as a key transcription factor mediating the adaptive cellular responses. Caspase-3 is a key apoptosis-related protease that plays a role in tumor growth and development. Studies have shown that caspase-3 could be regulated by HIF-1 alpha under pathological conditions. Therefore, HIF-1 alpha and caspase-3 expression may be related to the poor prognosis of tumors. In this study, we analyzed the possible relationships between these two signaling factors in correlation with the clinical behavior of PTC. Methods: We detected the expression levels of HIF-1 alpha and caspase-3 in 70 samples of PTC and para-cancerous tissues (control group) by immunohistochemistry (IHC). Furthermore, various clinicopathological parameters were assessed to determine their correlations with HIF-1 alpha and caspase-3 expressions. Results: First, HIF-1 alpha and caspase-3 expressions (60% and 37.1%, respectively) increased significantly in the PTC samples as compared to normal tissues (2.9% for both HIF-1 alpha and caspase-3) (p < 0.05) as determined by IHC. Second, although there was no significant difference between the expression of HIF-1 alpha and caspase-3 in regard to gender, age distribution, tumor size, lymph node metastasis, and BRAF(V600E) mutation (all p > 0.05), HIF-1 alpha and caspase-3 expressions were associated with capsule invasion and cell subtypes of PTC (p < 0.05). The percent positivity of caspase-3 expression in tall-cell variant (TCV) was the highest (63.6%). Third, HIF-1 alpha expression was positively correlated with that of caspase-3 (r(s) = 0.326; p < 0.05). Conclusions: Overexpression of HIF-1 alpha and caspase-3 is associated with carcinogenesis. These factors might serve as promising predictors of aggressive PTC. These findings also suggest their potential as therapeutic targets.