Tubby and related proteins are derived from a small family of novel genes. The carboxytermini of this family are highly conserved across a number of species including humans, mice, Caenorhabditis elegans, Arabidopsis, rice, and maize. Splicing defects in both tub and another member of the gene family, TULP1 (tubby-like protein 1), lead to phenotypes of retinal degeneration in mice and humans, respectively. We describe here the isolation of the human and mouse homologs of a new family member, TULP3. The cDNAs code for proteins of 442 and 460 amino acids, respectively. The level of identity between the human TULP3 and the mouse homolog is 69%, lower than that observed for the homologs of the other family members (96% for human and mouse TUB), and is higher at the amino- and carboxytermini than in the central region of the protein. Phylogenetically, TULP3 is the family member most closely related to TUB. Also, like TUB, it has a wider pattern of tissue expression than either TULP1 or TULP2. TULP3 is detected at high levels in human RNA from testis, ovaries, thyroid, and spinal chord. Tulp3 is also highly expressed in mouse RNA from eyes and adipose depots, tissues not tested in the human Northern analysis. We also report that TULP3 maps to human chromosome 12p13. The murine homolog, Tulp3, maps to the telomere of mouse chromosome 6.