Nursery depopulation has been described as an effective strategy for improving the performance of weaned pigs. In order to assess whether the strategy was effective under a wide range of conditions, a study was carried out on 34 farms in the USA. Four groups with different depopulation protocols were designed on the basis of the location of the depopulated facility (on site vs off site) and the period for which the nursery remained empty (seven days vs 14 days). The changes in average daily liveweight gain, percentage mortality, feed efficiency and treatment cost per pig produced were assessed 12 months before and after nursery depopulation. The ability to eliminate porcine reproductive and respiratory syndrome (PRRS) virus was examined by indirect fluorescent antibody testing of the nursery pigs. Significant improvements (P < 0.0001) were detected in both average daily gain and percentage mortality after depopulation when the differences within an individual group were analysed, but no significant differences (P > 0.14) were observed between the study groups. Serological testing indicated that antibodies to PRRS virus were still present in 14 of the 34 farms after depopulation.