The Pandemic (H1N1) 2009 virus is contagious and is believed to spread from human to human in much the same way as seasonal flu. The most common mechanisms by which it spreads are by droplets from coughs and sneezes of infected people, and also potentially touching a surface or the hand of a person contaminated with the virus and then touching one's eyes, nose or mouth, although there is no direct evidence for this. The Pandemic (H1N1) 2009 virus is more contagious than seasonal flu, and infected people are contagious for longer than had been thought. The US CDC had recommended that people should wait at least a day after their fever subsides (usually 3–4 days after the onset of symptoms) before resuming normal activities, but it has been found that they can continue to shed virus for several days after that. The contagiousness of the virus may change as it mutates.

The virulence of swine flu virus is mild and the mortality rates are very low. In mid-2009 the US Centers for Disease Control and Prevention (CDC) noted that most infections were mild, similar to seasonal flu, and that recovery tended to be fairly quick. The number of deaths as of September 2009 is sometimes misleadingly said to be a tiny fraction of the annual number of deaths from seasonal flu, but comparisons of human fatality figures with seasonal influenza are prone to underestimate impact of the pandemic and the pandemic H1N1/09 virus was in fact the dominant strain of influenza causing illness in the 2009/10 flu season.

Research carried out at Imperial College London has shown that, unlike seasonal flu, the Pandemic (H1N1) 2009 virus can infect cells deep in the lungs. Seasonal flu can only infect cells with receptor type a2-6 which are typically located in the nose and throat but H1N1/09 can also infect cells with receptor type a2-3. This may explain why some patients experience severe respiratory symptoms. (The H5N1 virus is also able to infect cells deep in the lungs with receptor type a2-3 but cannot infect cells with receptor type a2-6 making it less contagious than H1N1/09.)

From April 2009 to November 2009, in the US, 3,900 people have died of the H1N1 pandemic virus, sometimes compared to 36,000 people per year die from the "common flu", mostly in winter, although the former figure is for confirmed cases, whereas the latter is an estimate. The death rate of H1N1 in the US could be calculated as less than 0.02% from November 2009 figures from the CDC, and has been explicitly calculated as 0.026% in England.