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Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant mammalian enzyme in DNA base excision repair pathway that cleaves the DNA backbone immediately 5′ to abasic sites. In addition to its abasic endonuclease activity, APE1 has 3′ phosphatase and 3′–5′ exonuclease activities against DNA. We recently identified APE1 as an endoribonuclease that preferentially cleaves at UA, UG, and CA sites in single-stranded regions of RNAs and can regulate c-myc mRNA level and half-life in cells. APE1 can also endonucleolytically cleave abasic single-stranded RNA. Here, we show for the first time that the human APE1 has 3′ RNA phosphatase and 3′ exoribonuclease activities. Using three distinct RNA substrates, we show that APE1, but not RNase A, can remove the phosphoryl group from the 3′ end of RNA decay products. Studies using various site-directed APE1 mutant proteins (H309N …