Papillary thyroid carcinoma (PTC) has a high incidence, and its proper treatment remains challenging. Therefore, identifying PTC progression markers is essential. Here, using 16S RNA sequences, we analyzed the PTC intratumor microbiome and its role in tumor progression. Substantial microbial abundance was detected in PTC from all patients. The tumor bacterial diversity in patients with advanced lesions (T3/T4) was significantly higher than that in patients with relatively mild lesions (T1/T2). Importantly, we identified signatures of eight tumor bacterial taxa highly predictive of PTC invasion status. Hence, microbial host factors-independent of the genomic composition of the tumor-may determine tumor behaviors and patient outcomes. Furthermore, the correlation between specific bacterial genus and thyroid hormones or autoimmune thyroid disease-related antibodies may indicate the potential contribution of the microbiome in the relationship between autoimmune thyroid disease or irregular thyroid function and PTC progression, intervention of which might therefore be worth exploring for advancing oncology care.