Why does amoxicillin cause rash with mono?

Not certain: I do not believe that they have yet been able to determine exactly the mechanism why this occurs, but it does in many cases. It can actually be used as a 'poor man's' way to diagnose it. Not the best way though. This reaction is not a classic allergy and people can still use Amoxil (amoxicillin) safely again afterwards if they could use it beforehand. Ampicillin does the same but is not used as often.

Immune system: This has to do with how the virus and Amoxicillin interact with the immune system to cause the rash.

Altered immunity: During mononucleosis (ebv virus) infection, the virus infects b cells of the immune system and epithelial cells. This together with the presence of Amoxicillin can result in a type of drug rash which does not usually result in a true long-term allergic reaction to the drug.