Several regulators of G protein signaling (RGS) proteins contain a G protein γ -subunit-like (GGL) domain, which, as we have shown, binds to Gβ 5 subunits. Here, we extend our original findings by describing another GGL-domain-containing RGS, human RGS6. When RGS6 is coexpressed with different Gβ subunits, only RGS6 and Gβ 5 interact. The expression of mRNA for RGS6 and Gβ 5 in human tissues overlaps. Predictions of α -helical and coiled-coil character within GGL domains, coupled with measurements of Gβ binding by GGL domain mutants, support the contention that Gγ-like regions within RGS proteins interact with Gβ 5 subunits in a fashion comparable to conventional Gβ/Gγ pairings. Mutation of the highly conserved Phe-61 residue of Gγ 2 to tryptophan, the residue present in all GGL domains, increases the stability of the Gβ 3/Gγ 2 heterodimer, highlighting the importance of this residue to GGL/Gβ 5 association.