Despite being able to use the Bonzo coreceptor as efficiently as CCR5 in transfected cells, pediatric human immunodeficiency virus type 1 isolate P6 was unable to replicate in peripheral blood mononuclear cells (PBMC) lacking the CCR5 receptor. Furthermore, its replication in wild-type PBMC was completely inhibited by inhibitors of CCR5-mediated entry. Similarly, maternal isolate M6 could use CCR5, CXCR4, Bonzo, and other coreceptors in transfected cells but was completely sensitive to inhibitors of CCR5- and CXCR4-mediated entry when grown in PBMC. The ability of these viruses to use coreceptors in addition to CCR5 and CXCR4 in vitro was, therefore, irrelevant to their drug sensitivity in primary cells. We argue that CCR5 and CXCR4 should remain the primary targets for antiviral drug development, pending strong evidence to the contrary.