Abstract: A common objective of methods of systematic reserve selection has been to maximize conservation benefits—frequently current species richness—while reducing the costs of acquiring and maintaining reserves. But the probability that a reserve will lose species in the future is frequently not known because the minimum area requirements for most species have not been estimated empirically. For reserves within the Alleghenian-Illinoian mammal province of eastern North America, we empirically estimated the minimum area requirement of terrestrial mammals such that reserves should not lose species because of insularization. We compared this estimate to the actual size of 2355 reserves and reserve assemblages within the mammal province. The estimated minimum area requirement was 5037 km2 (95% CI: 2700–13,296 km2). Fourteen reserves and reserve assemblages were> 2700 km2, 9 were> 5037 km2, and 3 were> 13,296 km2. These 14 reserves accounted for 73% of the total area of reserves and 10% of the total area of the mammal province. Few reserves appear large enough to avoid loss of some mammal species without the additional cost of active management of habitat or populations. Immigration corridors and buffer zones that combine small reserves into assemblages totaling at least 2700 km2 may be the most efficient means of conserving mammals in these reserves.