One patient in the Lothians and another believed to be from Fife failed to respond to Tamiflu, one of the only treatments for the H1N1 virus.
Doctors around the world have seen a handful of cases where the virus has mutated to develop resistance to the drug.
NHS Lothian confirmed it has seen one patient with Tamiflu-resistant swine flu.
A spokesman for the Scottish Government said: "We are aware of Tamiflu resistance in two Scottish H1N1 patients.
"We have asked Health Protection Scotland to monitor the situation closely."