Chromosomal structural variants (SVs) are major contributors to cancer development. Although multiple methods exist for detecting SVs, they are limited in throughput, such as fluorescent in situ hybridization and targeted panels, and use RNA, which degrades in formalin-fixed, paraffin-embedded (FFPE) blocks and is unable to detect SVs that do not produce a fusion transcript. High-throughput chromosome conformation capture (Hi-C) is a DNA-based next-generation sequencing (NGS) method that preserves the spatial conformation of the genome, capturing long-range genetic interactions and SVs. We performed a retrospective study analyzing 71 FFPE specimens from 10 different solid tumors. We showed high concordance (98%) with clinical fluorescent in situ hybridization and RNA NGS in detecting known SVs. Furthermore, Hi-C provided insight into the mechanism of SV formation, including chromothripsis and extrachromosomal DNA, and detected rearrangements between genes and regulatory regions, all of which are undetectable by RNA NGS. Last, we detected SVs in 71% of cases in which previous clinical methods failed to identify a driver, of which 14% are clinically actionable based on current medical guidelines, and an additional 14% are not in medical guidelines but involve targetable biomarkers. Our data suggest that Hi-C is a robust and accurate method for genome-wide SV analyses from FFPE tissue and can be incorporated into current clinical NGS workflows.