The nucleotide sequence of the 5'-untranslated region (5'UTR) of the genome of foot-and-mouth disease virus (FMDV) R100, rescued after 100 passages of persistently infected BHK-21 cells, has been compared with that of the parental FMDV C-S8c1. The nucleotide sequence divergence between the two viruses in heteropolymeric regions is 1%. The few mutations located at the 5'-most terminal region (S fragment) and at the internal ribosome entry site (IRES) do not appear to affect significantly the tight secondary structure predicted for these RNA segments. Comparison of the 5'UTR of C-S8c1 or R100 RNA with that of other FMDV serotypes and subtypes indicates the presence of block deletions (or insertions) which do not correlate with the serological classification of FMDV. Remarkably, FMDV R100, a virus highly attenuated for mice and cattle, contains a polyribocytidylate (poly C) tract of about 420 nucleotides, 145 residues longer than its parental, virulent FMDV C-S8c1. This long poly C of R100 RNA includes a few uridine residues interspersed at fairly regular intervals. This is the longest highly homopolymeric tract described in a viral genome and, to our knowledge, in any informational biomolecule.