The mechanism of alternative AUG usage in foot-and-mouth disease virus is not completely understood. Using simple computational approaches, we evaluated the contributions of overall codon bias, quantitative codon bias, and %GC of the region between the two alternative AUGs, Region-La, as well as the nucleotide bias of the sequence context flanking each AUG with respect to translation initiation efficiency. For all serotypes of this virus, we found that only a small component of the effect of RNA secondary structure on ribosome scanning was due to the low %GC of Region-La. In addition, we found that the nucleotide bias of the context from position -4 to +6 flanking the AUG(2nd) had a negative correlation with the overall codon bias, and that a strong purine bias existed in this AUG(2nd)context. However, the quantitative codon bias of Region-La was seen to be significantly lower than that of Region-Lb (the sequence following AUG(2nd)) in all serotypes except SAT 1-3. Taken together, our results suggest that the low codon bias of Region-La might impair the translation initiation efficiency at the AUG(1st) in all serotypes except SAT 1-3, and the specific AUG(2nd) context might be used as a strong signal to initiate translation from the AUG(2nd) in all serotypes.