We present a method for the tissue-specific purification of protein complexes from the nematode C. elegans, based on cell-type specific biotinylation. To purify proteins from specific C. elegans tissues, we adapted a system based on in vivo biotinylation of a protein of interest. In this approach, a protein of interest is tagged with the 15 amino acid Avi-tag, which can be biotinylated in vivo by the BirA biotin ligase from Escherichia coli. The biotinylated bait protein and any associated proteins are then purified with streptavidin-coated beads, and their identities are determined by mass spectrometry.