The botulinum neurotoxins (BoNTs) are among the most lethal substances known to humankind. The work described herein examined the oral toxicity of the BoNTs and compared oral toxicity to in vitro stability in simulated gastrointestinal tract conditions. Our results demonstrate that a majority of the BoNTs tested were less stable in simulated intestinal fluid (SIF) as compared to simulated gastric fluid (SGF), and that oral toxicity correlated with the molecular weight of the BoNT complex. These results suggest that stability in the intestinal tract plays a critical role in the oral toxicity of the BoNTs.