The reoccurring region of seasonal hypoxia in the central basin of Lake Erie (“the dead zone”) has been of significant interest to researchers over the past several years. Surprisingly however, no efforts to characterize the endemic microbial community, responsible for the consumption of oxygen in this system, have been published. To understand how the microbial community may be interacting with this event, we have begun to characterize microbial members by using molecular tools. Phycoerythrin-rich cyanobacteria appear abundant and active in a narrow region ( 1.5 m) below the thermocline during hypoxic conditions, reaching abundances of greater than 105mL−1and being the primary agent releasing 1.5 mg O2 L−1above the daytime demands in this region. Sequencing of 16S rDNA amplicons, generated with universal eubacterial primer sets, from the Lake Erie's hypolimnion during seasonal oxygen depletion demonstrated that cyanobacteria, most closely related to phycoerythrin-rich Synechococcus spp., dominate during rapid drawdown of oxygen (0.083 mg L−1d−1in 2004) in this region. Analyses of another conserved marker of phylogeny (RuBisCO) has been used to confirm the presence of these cell types. Numerous distinct taxa of heterotrophic bacteria are also represented in the 16S library. The results of this study suggest that novel groups of cyanobacteria may persist within the Lake Erie dead zone during hypoxic conditions and, along with the heterotrophic community, strongly influence system geochemistry.