Enfuvirtide is a large protein that should be injected subcutaneously to ensure an appropriate absorption. Here we report the case of a transgender HIV-positive patient receiving enfuvirtide with an individualized background regimen of antiretroviral drugs, who had previously undergone liquid silicone oil injections. We performed US scan to detect silicone-free areas for following enfuvirtide injections. US can be useful in the correct management of those patients with liquid silicone oil soft tissue augmentation who require subcutaneously injected drugs.