Chrom3D is a computational platform for 3D genome modeling that simulates the spatial positioning of chromosome domains relative to each other and relative to the nuclear periphery. In Chrom3D, chromosomes are modeled as chains of contiguous beads, in which each bead represents a genomic domain. In this protocol, a bead represents a topologically associated domain (TAD) mapped from ensemble Hi-C data. Chrom3D takes as input data significant pairwise TAD-TAD interactions determined from a Hi-C contact matrix, and TAD interactions with the nuclear periphery, determined by ChIP-sequencing of nuclear lamins to define lamina-associated domains (LADs). Chrom3D is based on Monte Carlo simulations initiated from a starting random bead configuration. During the optimization process, TAD-TAD interactions constrain bead positions relative to each other, whereas LAD information constrains the corresponding bead toward the nuclear periphery. Optimization can be repeated many times to generate an ensemble of 3D genome models. Analyses of the models enable estimations of the radial positioning of genomic sites in the nucleus across cells in a population. Chrom3D provides opportunities to reveal spatial relationships between TADs and LADs. More generally, predictions from Chrom3D models can be experimentally tested in the laboratory. We describe the entire Chrom3D protocol for modeling a 3D diploid human genome, from the creation of input files to the final rendering of 3D genome structures. The procedure takes ∼18 h. Chrom3D is freely available on GitHub.