Human papilloma virus (HPV) has been suspected to play a role in the etiology of oral cancer for many years. Virulent forms of this virus are well documented to greatly increase risk of cervical cancer, and evidence suggests that the same viruses are present in the mouth. To date, however, studies reported in the literature vary tremendously with respect to the frequency at which HPV is found in oral cancers and non-diseased oral tissues such as the buccal mucosa. We hypothesized that the source of much of this variation was inconsistencies in the laboratory methods used to detect the virus. These methods are based on the polymerase chain reaction, and it is well known that this assay can be highly sensitive to contamination and other problems leading to inconsistency in the quantity of product produced. Our research study has evaluated several existing alternative methods for HPV typing, as well as modified some of these in an attempt to improve their performance. We have used cloned viruses as positive controls as well as a set of water and peripheral blood DNAs as negative controls. Assays have been performed in tandem by two laboratory scientists, with each blind to the results of the parallel assay. Our data demonstrate a fairly high degree of consistency for several but not all of our techniques when applied to these control specimens. Efforts are continuing to improve the repeatability of these assays for application to our molecular epidemiological studies or oral cancer.