Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD- tumors and 3,435 WGDþ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD- and WGDþ tumors. WGDþ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGDþ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGDþ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD-/WGDþ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution. Significance: These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.