The four patients were diagnosed with the flu during October and November.
Duke physicians discovered the resistant strain after some of the patients continued to test positive for the flu despite Tamiflu treatment. An antiviral resistance was confirmed by the laboratory at CDC Monday night.
Three of the patients have died, but officials say it is not clear whether their deaths were related to flu infections, because they had serious underlying medical conditions.
All the patients are adults. The fourth person is still hospitalized at Duke and doctors say they were able to treat her with Relenza.
Officials say a man and three women were on the same cancer unit at Duke University Medical Center when they contracted H1N1.
At this time, there is no indication of any antiviral-resistant cases outside of the affected hospital unit.
Officials say this is a rare cluster of cases. The CDC state officials and Duke doctors are investigating to figure out how the cases relate.
"There's no reason to infer that there's any difference in the severity of clinical illness associated with this mutation," State Epidemiologist Dr. Megan Davies said.
Also, doctors still don't know if the patients got the vaccine.
"The vaccine would still be very effective in protecting patients against this form of H1N1 and I think if anything just encourages us to encourage people to get vaccinated," Duke Infectious Diseases Dr. Cameron Wolfe said.
Doctors can effectively treat 99 percent of swine flu cases with Tamiflu. And usually all cases resistant to that drug so far have responded to Relenza.
"Tamiflu is still considered to be an effective drug for treatment of H1N1 flu." State Epidemiologist Dr. Zack Moore said.
The CDC says there have only been 21 such cases reported in the US and only 52 in the world.
For more information visit the DHHS Web site at www.dhhs.state.nc.us.