Massively parallel sequencing allows for rapid sequencing of large numbers of sequences in just a single run. Thus, 16S ribosomal RNA (rRNA) amplicon sequencing of complex microbial communities has become possible. The sequenced 16S rRNA fragments (reads) are clustered into operational taxonomic units and taxonomic categories are assigned. Recent reports suggest that data pre-processing should be performed before clustering. We assessed combinations of data pre-processing steps and clustering algorithms on cluster accuracy for oral microbial sequence data.