Exportin 5 (XPO5) is a microRNA (miRNA)-related nuclear export protein, and its disorder may lead to the dysregulation of miRNAs. Recent studies have demonstrated that the aberrant expression of XPO5 might participate in carcinogenesis in certain cancers. However, there is only limited information of XPO5 in thyroid cancer (TC) development. In our study, we quantified the expression level of XPO5 by real-time polymerase chain reaction (PCR) in 64 TC patients' cancer tissues and adjacent normal tissues. After confirming the XPO5 expression, we evaluated the association between XPO5 potential functional single-nucleotide polymorphisms (SNPs) and risk of TC in a Chinese population (1140 cases vs 1230 controls). Finally, luciferase assays were performed to investigate the function of the SNP in XPO5 3' untranslation region. The message ribonucleic acid (RNA) levels of XPO5 were significantly lower in cancer tissues than normal tissues (P=0.004). In SNPs screening, only 1 noble SNP rs11077 was identified in XPO5 functional region. The results in our case-control study also confirmed that XPO5 rs11077 was significantly associated with onset of TC (GT/GG vs TT P=0.035, adjusted odds ratio = 1.25, 95% confidence interval = 1.02-1.54). The adverse influence of this polymorphism was mainly observed in age >45 years (P=0.028), female (P=0.020), T1 staging (P=0.026), N1 (P=0.038), metastasis (P=0.031 M0, and P=0.035 for M1), and early stage (I+II) (P=0.021). A following luciferase test revealed the critical role of rs11077 for triggering the XPO5 expression. Furthermore, patients with G allele of rs11077 showed lower XPO5 expression level. XPO5 SNP rs11077 influences the expression of XPO5, and this SNP could also be a potential biomarker for the diagnosis of TC in clinical, especially in Chinese population.