U6 snRNA is a component of the major class of small RNA-protein complexes, the Sm snRNPs, present in mammalian cell nuclei. Here we report that a substantial fraction (about 10%) of U6 RNA from human and mouse cells is associated with another lupus antigen, the 50 kd La protein. The La-bound U6 subpopulation is characterized by 3' end heterogeneity and partial undermethylation. These U6 molecules have U-rich 3' termini that could be responsible for their selective association with the La protein. The question of whether they are precursors to the major U6 RNAs found in Sm snRNPs is discussed.