Despite the potentially profound impact of genetically modified crops on agriculture and the environment, we know little about their long-term effects. Transgenic crops that produce toxins from Bacillus thuringiensis (Bt) to control insects are grown widely, but rapid evolution of resistance by pests could nullify their benefits. Here, we present theoretical analyses showing that long-term suppression of pest populations is governed by interactions among reproductive rate, dispersal propensity, and regional abundance of a Bt crop. Supporting this theory, a 10-year study in 15 regions across Arizona shows that Bt cotton suppressed a major pest, pink bollworm (Pectinophora gossypiella), independent of demographic effects of weather and variation among regions. Pink bollworm population density declined only in regions where Bt cotton was abundant. Such long-term suppression has not been observed with insecticide sprays, showing that transgenic crops open new avenues for pest control. The debate about putative benefits of Bt crops has focused primarily on short-term decreases in insecticide use. The present findings suggest that long-term regional pest suppression after deployment of Bt crops may also contribute to reducing the need for insecticide sprays.