FKBP12 is an 11.8-kDa protein that binds the potent immunosuppressants FK506 and rapamycin. When bound to FK506, FKBP12 forms an inhibitory complex with calcineurin and interferes with signal transduction in activated T lymphocytes. In studying human FKBP12 cDNAs and the human FKBP12 gene, we found that three distinct transcripts can encode human FKBP12. The transcripts, which we designate FKBP 12A, 12B and 12C, contain identical open reading frames, but vary in abundance and are distinguished by unique 3' untranslated regions. The mature transcripts derive from either four or five exons and are generated by the differential use of one splice junction and three cleavage-polyadenylation sites within FKBP12. FKBP12A and 12B populations increase in abundance and/or stability when T-cell populations are mitogenically activated in vitro, implying that one result of T-cell stimulation is increased demand for the FKBP12 message. These transcripts are also present in a variety of human tissues, suggesting that FKBP12 and/or the mRNAs encoding it might affect physiological function(s) in a diverse array of cells.