Abstract Context.—Phosphatase of regenerating liver (PRL) 3 messenger RNA (mRNA) was reported to express in human colorectal, gastric, ovarian, breast, and hepatic cancers. Objective.—To examine the expression of PRL-1 and PRL-3 mRNAs in human esophageal squamous cell carcinoma (ESCC). Design.—Expression of PRL-1 and PRL-3 mRNA was examined with reverse transcriptase–polymerase chain reaction in fresh tissue collected from 40 cases of ESCC with matched lymph node metastasis in 21 cases. The association of expression of PRL-1 and PRL-3 mRNAs with clinicopathologic parameters was analyzed. Results.—The frequencies of PRL-1 and PRL-3 mRNA expression were significantly higher in ESCC than in normal esophageal tissue (P = .001; P = .01) and also significantly higher in ESCC with lymph node metastasis than in those without lymph node metastasis (P = .01; P = .03). The levels of PRL-1 and PRL-3 mRNA expression were significantly higher in ESCC with lymph node metastasis than in those without lymph node metastasis (P = .04; P = .04). The frequencies and levels of PRL-1 and PRL-3 mRNA expression were correlated with the later stages but not with tumor differentiation, tumor location in the esophagus, patient's sex, and age. Conclusions.—PRL-1 and PRL-3 mRNAs may be involved in and used to predict the metastasis of ESCC. The possibility of using PRL-1 and PRL-3 as the therapeutical target is also discussed.