Abstract: Histone variants and histone modification complexes act to regulate the functions of chromatin. In Saccharomyces cerevisiae the histone variant H2A.Z is encoded by HTZ1. Htz1 is dispensable for viability in budding yeast, but htz1Delta is synthetic sick or lethal with the null alleles of about 200 non-essential genes. One of the strongest of these interactions is with the deletion of SET3, which encodes a subunit of the Set3/Hos2 histone deacetylase complex. Little is known about the functions of Set3 and interpreting these genetic interactions remains a highly challenging task. Here we report the results of a forward genetic screen to identify bypass suppresssors of the synthetic slow-growth phenotype of htz1Delta set3Delta. Among the identified loss-of-function suppresssors are genes encoding subunits of the HDA1 deacetylase complex, the SWR1 complex, the H2B deubiquitination module of SAGA, the proteasome, Set1, and Sir3. This constellation of suppresssor genes is uncommon among the global set of htz1Delta synthetic interactions. BDF1, AHC1, RMR1, and CYC8 were identified as high-copy suppresssors. We also identified interactions with SLX5 and SLX8, encoding the sumoylation-targeted ubiquitin ligase complex. In the context of htz1Delta set3Delta, suppresssors in the SWR1 and the H2B deubiquitination complexes show strong functional similarity, as do suppresssors in the silencing genes and the proteasome. Surprisingly, while both htz1Delta set3Delta and swr1Delta set3Delta have severe slow-growth phenotypes, the htz1Delta swr1Delta set3Delta triple mutant grows relatively well. We propose that Set3 has previously unrecognized functions in the dynamic deposition and remodeling of nucleosomes containing H2A.Z.