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Background: Drosophila Phosphatase of Regenerating Liver-1 (PRL-1) is the only homolog of the mammalian PRLs with which it shares high sequence and structural similarities. Whilst PRLs are most notable for their high expression in malignant cancers and related promotion of cancer progression, the specific biological functions of the PRLs remain largely elusive. Methods: Here, using a gain-of-function approach, we found that PRL-1 functions during wing vein development in Drosophila melanogaster (Drosophila). Overexpression of Drosophila PRL-1 caused dose-dependent wing vein proliferation. Results: Genetic screening of the main TGF-β signaling factors, Mad and Smox, showed that the RNAi-mediated knockdown of Mad could alleviate the extra vein phenotype caused by overexpressed PRL-1 and lead to loss of the posterior section of longitudinal veins. However, knockdown of Smox resulted in an identical phenotype with or without the overexpression of Drosophila PRL-1. Clonal analyses revealed that overexpression of PRL-1 led to decreased expressions of activated phospho-Mad protein, as measured by immunostaining. Real-time PCR showed that the transcriptional levels of Smox were significantly increased upon overexpression of the Drosophila PRL-1 in wing discs, with a dose dependent effect. Conclusions: We propose that the main function of Drosophila PRL-1 in wing development is to affect the phospho-Mad levels and Smox transcriptional levels, therefore influencing the competitive balance for Medea between Mad and Smox. Our study demonstrates the novel role for Drosophila PRL-1 in regulating TGF-β signaling to influence wing vein formation which may also provide insight into the understanding of the relationship between PRLs and TGF-β signaling in mammals.