The 2016 World Health Organization classification recognized “high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements” (double/triple-hit lymphoma [DTHL]) and “high-grade B-cell lymphoma, not otherwise specified,” which includes non-DTHL with a “blastoid” or “intermediate” cytology. Although extensively studied, many questions remain, including which cases belong in these categories, which factors mitigate their adverse prognosis, and when to perform fluorescence in situ hybridization studies. Therefore, the clinicopathologic features of 187 large B-cell lymphomas with MYC, BCL2, and BCL6 fluorescence in situ hybridization were investigated. There were 47 DTHLs, 36 cases with MYC and BCL2 and/or BCL6 extra signals (ES) and/or rearrangements (ES group, excludes DTHLs), 9 with MYC rearrangements only (single-hit lymphoma), and 95 with no MYC abnormalities (NM). Patients with DTHLs, but not single-hit lymphomas, had a significantly worse prognosis compared with those with NM (P=0.0079). The ES group with at least 1 rearrangement had a worse prognosis compared with the NM/ES without rearrangement group (P<0.02). Blastoid, but not intermediate cases, were enriched in DTHLs (P<0.0001) and had a significantly worse prognosis even among DTHLs (P=0.0282). The prognosis of the diffuse large B-cell lymphoma and intermediate groups was similar. International Prognostic Index score was of prognostic importance for the entire group and for DTHLs (P=0.0074). About 93% of DTHLs were of GCB type but 24% had <40% MYC+ cells. Among the DTHLs, MYC+BCL2+ double expressor cases had a worse prognosis (P=0.0328). These results highlight the importance of morphologic, phenotypic, and clinical variations among the DTHLs and suggest that a diagnosis equivalent to DTHL should not be made based solely on ES for MYC and BCL2 and/or BCL6.