The HIV-1-envelope (Env) spike is a conformational machine that switches between multiple prefusion conformations to a postfusion conformation to facilitate HIV-1 entry. Extensive interest has focused on the prefusion mature closed conformation, as it is the target of neutralizing antibodies. One hall-mark of the prefusion conformation is the recognition by the small molecule entry inhibitor, BMS-378806, and its derivative BMS-626529, currently in clinical trial. BMS-626529 has been shown to inhibit HIV infection with an EC50 of 1–10 nM in vivo but the mechanism of inhibition remains unclear. Here, we obtained the crystal structures of the soluble mimic of HIV-1 Env, BG505 SOSIP.664 bound by antibodies 35O22 and PGT122 and small molecule BMS-378806 and BMS-626529 at 3.8 and 3.7 [Latin Capital Letter A with Ring above and Acute] resolution, respectively. The structures revealed the location and orientation of binding of these lead candidate HIV-1 entry inhibitors. They bind gp120 at a surface pocket adjacent to the Phe 43 cavity where CD4 inserts. The structures explained the resistance phenotypes reported. Together with biophysical and antigenic characterization, the structures also provide a mechanism of inhibition for these small molecules: they inhibit CD4 binding and CD4-induced conformational changes through an allosteric competitive mechanism. Moreover, the chemical details of BMS- 378806 and BMS-626529 interactions should allow for their structure- based optimization.