The life cycle transformation of the protozoan parasite Leishmania from promastigote to amastigote is accompanied by changes in the level of expression of a number of proteins whose function may be necessary for parasite survival in the sandfly vector or mammalian host. To genetically characterize these proteins, we have cloned and characterized cDNA sequences that vary in abundance during the life cycle of Leishmania major. One sequence (P100/11E) encodes a poly(A+) RNA whose abundance is markedly elevated in promastigotes of L. major. The DNA sequence of the P100/11E cDNA predicts an acidic polypeptide of Mr = 32,000 which shows 40-46% similarity to the superfamily of reductase proteins including 2,5-diketo-D-gluconic acid reductase, aldose reductase, aldehyde reductase, and rho-crystallin. The P100/11E sequence of L. major contains the IPKS motif located at the active site of both aldose and aldehyde reductases. The P100/11H sequence was expressed in Escherichia coli, and the purified polypeptide was used to raise rabbit antisera which detect a protein of Mr = 35,000 in promastigotes of L. major. These results provide direct genetic evidence that L. major expresses a sequence homologous to the reductase superfamily as a developmentally regulated gene product in promastigotes.