The capsid precursor (P1-2A) of foot-and-mouth disease virus is processed by the 3C protease (3Cpro) to VP0, VP3 and VP1 plus 2A. During capsid assembly, the VP0 is cleaved to VP4 plus VP2. Single amino acid changes in a conserved motif (YCPRP) near the C-terminus of VP1 can block processing of the capsid precursor by the 3Cpro, although the cleavage sites are located hundreds of amino acids distant from this motif, presumably due to misfolding. In contrast, we show here that the absence of the VP4 sequence during the synthesis of the capsid precursor does not affect its subsequent processing. Cleavage of this truncated precursor by 3Cpro at the VP3/VP1 and VP2/VP3 junctions occurred efficiently. Thus, in contrast to the presence of the YCPRP motif in VP1, there are no critical motifs near the N-terminus of the precursor, within VP4, required for correct cleavage by 3Cpro. •FMDV capsid precursor (P1-2A) is cleaved by 3C protease prior to capsid assembly.•Single residue changes near the C-terminus of P1-2A can prevent this processing.•Precise deletion of the entire VP4 coding sequence does not affect processing.•There are no critical motifs near the N-terminus of P1-2A required for processing.•Different regions of P1-2A have distinct but critical functions in virus assembly.