Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated β-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer. Display omitted •The GTP-bound K-Ras4B catalytic domain can form stable homodimers•The K-Ras4B predicted β-sheet dimer interface overlaps the effectors' binding site•The K-Ras4B α3/α4 helical dimer interface may promote Raf dimerization•The two interfaces may illuminate K-Ras4B nanocluster formation Muratcioglu et al. show that GTP-bound but not GDP-bound K-Ras4B catalytic domain can form stable homodimers. Modeling reveals two major dimer interfaces. The highly populated β-sheet interface is at the Switch I/effector binding regions. The second major dimerization mode involves helical interfaces at the C-terminal allosteric lobe of the G domain.