All botulinum toxins (BoNTs, types A-G) inhibit synaptic transmitter release from motoneurons, and thus result in respiratory arrest and death. Rapid treatment with anti-BoNT antibodies can prevent progression, but recovery still requires weeks on a ventilator. Even after recovery, there is a potential for persistent fatigue in some cases of botulism even years after the insult, possibly because of motoneuron dropout for previously unknown reasons. Unique among BoNTs, the C-type (BoNT/C) cleaves two proteins involved in neurotransmitter release, syntaxin and SNAP-25, and induces apoptotic cell death in cultured cerebellar neurons. It is not clear, however, whether BoNT/C also affects neurons that encounter toxin in vivo, namely motoneurons. Here, we provide experimental evidence that BoNT/C causes a slow degeneration of motoneurons both in vitro and in vivo. This novel form of BoNT/C-induced cell death may require new treatment strategies.