ABSTRACT The anaphase-promoting complex (APC) is required for mitotic progression and genomic stability. Recently, we demonstrated that the APC is also required for mitotic chromatin assembly and longevity. Here, we investigated the role the APC plays in chromatin assembly. We show that apc5 CA mutations genetically interact with the CAF-I genes as well as ASF1 , HIR1 , and HIR2 . When present in multiple copies, the individual CAF-I genes, CAC1 , CAC2 , and MSI1 , suppress apc5 CA phenotypes in a CAF-1- and Asf1p-independent manner. CAF-I and the APC functionally overlap, as cac1Δ cac2Δ msi1Δ ( caf1Δ ) cells expressing apc5 CA exhibit a phenotype more severe than that of apc5 CA or caf1Δ . The Ts − phenotypes observed in apc5 CA and apc5 CA caf mutants may be rooted in compromised histone metabolism, as coexpression of histones H3 and H4 suppressed the Ts − defects. Synthetic genetic interactions were also observed in apc5 CA asf1Δ cells. Furthermore, increased expression of genes encoding Asf1p, Hir1p, and Hir2p suppressed the apc5 CA Ts − defect in a CAF-I-dependent manner. Together, these results suggest the existence of a complex molecular mechanism controlling APC-dependent chromatin assembly. Our data suggest the APC functions with the individual CAF-I subunits, Asf1p, and the Hir1p and Hir2p proteins. However, Asf1p and an intact CAF-I complex are dispensable for CAF-I subunit suppression, whereas CAF-I is necessary for ASF1 , HIR1 , and HIR2 suppression of apc5 CA phenotypes. We discuss the implications of our observations.