Cu-S-based materials with sphalerite-derivative structures are of interest for their complex cationic distribution, rich crystal structure chemistry, and potential in energy conversion and optoelectronic applications. In this study, a new member of colusite, Cu26Ti2Sb6S32, was designed by exploiting the key role of d0 (T) and d10 (M) cations in the sphalerite-derivative structure of Cu26T2M6S32 colusites. We succeeded to incorporate d0 Ti4+ and d10 Sb5+ into T and M sites, respectively, with a tetrahedral coordination rarely found for these two cations in solid-state chemistry. The synthesis produced the first semiconducting compound with the colusite structure. In addition, Cu26Ti2Sb6S32 exhibits a low lattice thermal conductivity. Partial substitution of Ge for Sb increased the hole carrier concentration, leading to an enhanced thermoelectric power factor and dimensionless figure of merit (ZT of 0.9 at 673 K). The electronic and phonon structures, responsible for the high thermoelectric performance, were elucidated by first-principles calculations.