Somatic mutations have important biological ramifications while exerting substantial rate, type, and genomic location heterogeneity. Yet, their sporadic occurrence makes them difficult to study at scale and across individuals. Lymphoblastoid cell lines (LCLs), a model system for human population and functional genomics, harbor large numbers of somatic mutations and have been extensively genotyped. By comparing 1,662 LCLs, we report that the mutational landscape of the genome varies across individuals in terms of the number of mutations, their genomic locations, and their spectra; this variation may itself be modulated by somatic trans-acting mutations. Mutations attributed to the translesion DNA polymerase η follow two different modes of formation, with one mode accounting for the hypermutability of the inactive X chromosome. Nonetheless, the distribution of mutations along the inactive X chromosome appears to follow an epigenetic memory of the active form. Display omitted •Analysis of 885,655 mutations from 1,662 lymphoblastoid cell lines (LCLs)•Inter-individual variation in the rate and genomic distribution of mutations•BCL6 is a candidate modulator of the mutational landscape in LCLs•Hypermutation of the inactive X chromosome is attributed to DNA polymerase η An analysis of the mutational landscape in 1,662 individuals reveals genome-wide variation in mutational loads, genomic distribution, and signatures, all of which appear to be modulated by somatic mutations in trans. The inactive X chromosome is unusual in bearing an excess of replication-timing-uncoupled DNA polymerase η-mediated mutations.