MYC-rearranged high-grade B-cell lymphoma (HGBCL) patients with concurrent BCL2 rearrangements (HGBCL-MYC/BCL2) often have a poor prognosis with standard chemoimmunotherapy and may benefit from more intensified regimens. Conventional fluorescence in situ hybridization (FISH) is the gold standard for detecting rearrangements, but it has several limitations. This study compared DNA- and RNA-sequencing with FISH to detect clinically relevant rearrangements in HGBCL. Archived formalin-fixed, paraffin-embedded samples from 34 patients who underwent FISH testing were analyzed using targeted DNA- and RNA-sequencing. DNA- and RNA-sequencing identified six and five out of the 12 MYC rearrangements detected by FISH, 10 and 6 out of 10 FISH-detectable BCL2 rearrangements, and 13 and 10 out of the 18 FISH-detectable BCL6 rearrangements. When combining DNA- and RNA-sequencing (integrated NGS), the sensitivity for detecting MYC, BCL2, and BCL6 rearrangements was 58.3%, 100%, and 73.7%, respectively. Both DNA- and RNA-sequencing detected the EIF4A2::BCL6 fusion missed by FISH. FISH identified 12 HGBCL-MYC/BCL2 out of 34 cases, while the integrated NGS strategy identified 7 cases, with 5 cases showing discordant results (41.7%). Additionally, patients with DLBCL/HGBCL-MYC/BCL2 had significantly shorter overall survival than other patients. Our results suggest that an integrated NGS strategy should not replace FISH or be routinely used in the workup to detect the clinically relevant rearrangements in HGBCL. It may serve as a complement to FISH testing when FISH shows negative results.