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In GWA studies, CLEC16A has been identified as a risk gene for several major autoimmune diseases, including multiple sclerosis (MS). We show that CLEC16A is increased in MS and functionally links to HLA-II, and uncovered the molecular mechanism of CLEC16A as key regulator of HLA-II antigen presentation. We used the human melanoma cell line MelJuSo and primary moDC as APC models to silence CLEC16A with different siRNA and lentiviral shRNA. CLEC16A knockdown in MelJuSo cells and moDC resulted in cytoplasmic dispersion and strong accumulation of HLA-II+ late endosomes, suggesting impaired formation of multivesicular late endosomal compartments, i.e. MIIC. Indeed, in CLEC16A shRNA transductants, MIIC contained no or a few abnormally enlarged internal vesicles and showed an increased number of HLA-II molecules as compared to scrambled shRNA transductants of MelJuSo cells. CLEC16A associated with Rab7-interacting lysosomal protein (RILP) and the homotypic fusion and protein sorting (HOPS) complex, two members of the dynein motor complex regulating late endosomal trafficking and maturation. In addition, CLEC16A silencing disrupted RILP-mediated recruitment of HLA-II+ late endosomes to perinuclear regions. We reveal direct involvement of CLEC16A in the machinery regulating late endosomal processing of HLA-II. This novel C-type lectin function supports a pathogenic role of CLEC16A in autoimmune disease by promoting HLA-II antigen presentation via the formation of MIIC.