The small ribonucleoproteins recognized by anti-La sera consist mainly of RNA polymerase III products complexed with an antigenic cellular protein of 50 kd. A biochemical procedure for purifying the La protein from HeLa cells is described. The interaction of the isolated protein with a collection of model tRNA precursors, generated by ligation of specific oligonucleotides to the 3' terminus of yeast tRNAPhe, was studied. The most stable complexes are formed with adducts possessing three or four terminal uridylate residues. Addition of a terminal phosphate, fragmentation of the RNA, or substitution of other nucleotides reduce the affinity for the La protein. The preferred terminal sequence recognized and bound by La protein is homologous to the transcriptional termination signal for RNA polymerase III.