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The prostate-specific membrane antigen (PSMA), a product of the folate hydrolase (FOLH1) gene, is highly expressed as a largely extracellular membrane-anchored protein in malignant prostate tissues and in nonprostatic tumor neovasculature. Treatment of prostate cancer LNCap cells with spliceswitching oligonucleotides (SSOs) modulated splicing of FOLH1 pre-mRNA from the full-length PSMA splice variant to three splice variants: the cytoplasmic PSM′, alternatively spliced at exon 1, and the previously unexamined PSMAΔ6 and PSMAΔ18 variants, which lack exons 6 and 18, respectively. Application of SSOs decreased membrane PSMA levels and increased PSM′, PSMAΔ6, and PSMAΔ18 transcripts. As a result, PSM′ protein was translocated to the cytoplasm, and switching to PSMAΔ6 and PSMAΔ18 downregulated PSMA expression. NAALADase assays showed that PSM′ retained enzymatic activity. PSMAΔ6 and PSMAΔ18 were not active, presumably due to a change in a reading frame that eliminated the NAALDase active site or the dimerization domain or both in these proteins.