Tumor genomes evolve through a selection of mutations. These mutations may complement each other to promote tumorigenesis. To better understand the functional interactions of different processes in cancer, we studied mutation data of a set of tumors and identified significantly co-mutated pathways. Fisher's exact test is a standard approach that can be used to assess the significance of the joint dysregulation of pathways pairs across a patient population. We developed a robust test to identify co-occurrence using DNA mutations, which overcomes deficiencies of the Fisher's exact test by taking into account the large variability in overall mutation load and sequencing depth. Applying our method to a study of six common cancer types, we identify enrichment of co-mutated signal transduction pathways such as IP3 synthesis and PI3K and pairs of co-mutated pathways involving other processes such as immunity and development. We observed enrichment of clonal co-mutation of the proteasome and apoptosis pathways in colorectal cancer, which suggests potential mechanisms for immune evasion.