RGS proteins are GTPase activators for heterotrimeric G proteins. We report here the 2.8 Å resolution crystal structure of the RGS protein RGS4 complexed with G(iα1)-Mg2+-GDP-AlF4. Only the core domain of RGS4 is visible in the crystal. The core domain binds to the three switch regions of G(iα1), but does not contribute catalytic residues that directly interact with either GDP or AlF4. Therefore, RGS4 appears to catalyze rapid hydrolysis of GTP primarily by stabilizing the switch regions of G(iα1), although the conserved Asn-128 from RGS4 could also play a catalytic role by interacting with the hydrolytic water molecule or the side chain of Gln-204. The binding site for RGS4 on G(iα1) is also consistent with the activity of RGS proteins as antagonists of G(α) effectors.