The mannose 6‐phosphate receptor MPR46 mediates sorting of lysosomal enzymes and recycles between the trans‐Golgi network and endosomes. We characterized the retrograde transport of MPR46 from endosomes to the TGN by an in vitro transport assay using mouse fibroblast cell lines. Sulfation of a modified MPR46 upon entering the TGN is measured. The in vitro retrograde transport is time‐, temperature‐, ATP‐ and cytosol‐dependent. Transport requires the SNARE proteins Vti1a and Syntaxin 16 and the Rab family member Rab6. The transport is sensitive to GTPγS, brefeldin A and independent of TIP47. These data indicate that MPR46 follows an early endosome‐to‐TGN route. Transport is inhibited by MPR46 tail peptide comprising the acidic cluster‐di‐leucine sorting motif to which adaptor proteins AP‐1 and AP‐3 bind. Transport depends on cytosolic AP‐3, but not on cytosolic AP‐1. Residual membrane‐associated AP‐1 may have masked a requirement for cytosolic AP‐1. The competence of membranes from AP‐1‐deficient cells for endosome‐to‐TGN transport in vitro was severely compromised.