Since the last pandemic nearly 40 years ago, we have observed dramatic changes in social and ecological factors thought to facilitate emergence of a pandemic-capable strain. Surging human and bird populations in Asia have increased the frequency of contact between birds and humans—and these changes might facilitate emergence by permitting “crossing over” of a mutated avian influenza to humans, or by allowing human and avian influenzas to reassort in the same animal host. Already, the cases of human infection with avian influenzas are mounting. From 2003 to February 2, 2006, there have been 161 documented cases of and 86 deaths due to highly pathogenic H5N1 avian influenza infections in humans [ 4]. Serologic evidence indicates that humans have been infected with many types of avian influenzas [ 9], not just the easily ascertained, highly pathogenic H5N1. Though each human case of avian influenza, acquired from a bird exposure, has a low probability of creating a virus strain capable of pandemic spread, H5N1 influenza has probably spread from human to human within one family [ 10], and several additional cases may also have involved human-to-human transmission [ 11]. In considering the overall risk that a pandemic strain will emerge in a particular time period, the relevant figure is not the risk that a single infection will lead to a pandemic, but the probability that any of the human or animal cases occurring over that period will give rise to a strain capable of sustained human-to-human transmission and that the strain will begin spreading in people. If a pandemic-capable H5N1 strain emerges once in humans and is contained, is it likely to emerge again? One might hope to look to history for evidence on this question. Genetic evidence of multiple reassortment events or mutations early in the 1968 H3N2 pandemic [ 12] is consistent with the possibility of multiple introductions, but does not demonstrate this conclusively. We are not aware of such evidence for other pandemics, none of which were contained. However, one might expect that if multiple introductions did occur but none were contained, the evidence for such introductions might be difficult to detect because of depletion of susceptible hosts by the first uncontained introduction, competitive exclusion by the most transmissible of the introduced strains, or other factors. When a strain emerges in one locale, the fundamental processes of bird-to-bird and bird-to-human transmission that generate introductions need not change elsewhere. Thus, a single emergence may neither increase nor decrease the chance that another emergence will happen the next day or week, nearby or in another country. Under the assumption that the risk (or hazard) of emergence remains constant over time, if one introduction is likely in a given period, then multiple introductions are also likely. Figure 1 shows the relationship between the risks of zero, one, or more than one introduction under the constant hazard assumption (which generates a Poisson distribution of introductions in a given period). As the expected number of introductions in a given period, which we call v, increases from zero, the likelihood of a single introduction also rises (along with the likelihood of more than one); as it increases further, a single introduction becomes less likely and multiple introductions more likely. Figure 1 Probabilities of Zero, One, or Two or More Events (Introductions of a Pandemic-Capable Strain) When the Expected Number of Events Ranges from Zero to Ten, under a Constant Hazard (Poisson Distribution) More plausibly, one might expect that the first introduction is likely to occur because something has changed in the virus circulating in birds: the avian strain has increased in prevalence in a particular area [ 2, 3, 13], spread to new geographic areas [ 2], or evolved in such a way that it is better suited to human transmission [ 14]. This last scenario—that the virus could evolve within birds to a form that is capable of pandemic transmission in humans—has recently become more plausible given evidence that the 1918 pandemic H1N1 strain was transferred from birds to humans without reassortment [ 15]. If the hazard of introductions depends on any of these factors, then observing a single introduction would signal that the risk of further introductions had increased substantially, and introductions would be clustered. Under either assumption, if we believe an introduction is likely, then we must also expect a high risk of multiple introductions.