The HTLV-1 singly spliced open reading frame I protein, p12^I, is highly unstable and appears to be necessary for persistent infection in rabbits. Here we demonstrate that p12^I forms dimers through two putative leucine zipper domains and that its stability is augmented by specific proteasome inhibitors. p12^I is ubiquitylated, and mutations of its unique carboxy-terminus lysine residue to an arginine greatly enhance its stability. Interestingly, analysis of 53 independent HTLV-1 strains revealed that the natural p12^I alleles found in ex vivo samples of tropical spastic paraparesis-HTLV-1-associated myelopathy patients contain a Lys at position 88 in some cases, whereas arginine is consistently found at position 88 in HTLV-1 strains from all adult T-cell leukemia-lymphoma (ATLL) cases and healthy carriers studied. This apparent segregation of different alleles in tropical spastic paraparesis-HTLV-associated myelopathy and ATLL or healthy carriers may be relevant in vivo, since p12^I binds the interleukin-2 receptor β and γ_c chains, raising the possibility that the two natural alleles might affect differently the regulation of these molecules.