The most prevalent route of HIV-1 infection is across mucosal tissues after sexual contact. Langerhans cells (LCs) belong to the subset of dendritic cells (DCs) that line the mucosal epithelia of vagina and foreskin and have the ability to sense and induce immunity to invading pathogens(1). Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection(2). Notably, LCs form a protective barrier against HIV-1 infection and transmission(3-5). LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules(5). However, the underlying molecular mechanism of HIV-1 restriction in LCs remains unknown. Here we show that human E3-ubiquitin ligase tri-partite-containing motif 5 alpha (TRIM5 alpha) potently restricts HIV-1 infection of LCs but not of subepithelial DC-SIGN+ DCs. HIV-1 restriction by TRIM5 alpha was thus far considered to be reserved to non-human primate TRIM5 alpha orthologues(6-9), but our data strongly suggest that human TRIM5 alpha is a cell-specific restriction factor dependent on C-type lectin receptor function. Our findings highlight the importance of HIV-1 binding to Langerin for the routeing of HIV-1 into the human TRIM5 alpha-mediated restriction pathway. TRIM5 alpha mediates the assembly of an autophagy-activating scaffold to Langerin, which targets HIV-1 for autophagic degradation and prevents infection of LCs. By contrast, HIV-1 binding to DC-SIGN(+) DCs leads to disassociation of TRIM5 alpha from DC-SIGN, which abrogates TRIM5 alpha restriction. Thus, our data strongly suggest that restriction by human TRIM5 alpha is controlled by C-type-lectin-receptor-dependent uptake of HIV-1, dictating protection or infection of human DC subsets. Therapeutic interventions that incorporate C-type lectin receptors and autophagy-targeting strategies could thus provide cell-mediated resistance to HIV-1 in humans.