Using neXtProt release 2019-01-11, we manually curated a list of 1837 functionally uncharacterized human proteins. Using OrthoList 2, we found that 270 of them have homologues in Caenorhabditis elegans, including 60 with a one-to-one orthology relationship. According to annotations extracted from WormBase, the vast majority of these 60 worm genes have RNAi experimental data or mutant alleles, but manual inspection shows that only 15% have phenotypes that could be interpreted in terms of a specific function. One third of the worm orthologs have protein-protein interaction data, and two of these interactions are conserved in humans. The combination of phenotypic, protein-protein interaction, and gene expression data provides functional hypotheses for 8 uncharacterized human proteins. Experimental validation in human or orthologs is necessary before they can be considered for annotation.