To explore alternative cervical cancer screening approaches in an underserved population, we compared the performance of human papillomavirus (HPV) DNA assays in combination with different sample collection methods for primary cervical screening in the Mississippi Delta region. Three specimens were collected from women aged 26 to 65 years who were either routinely undergoing screening (n ؍ 252) or not (n ؍ 191): clinician-collected cervical specimens, clinician-collected cervicovaginal specimens, and self-collected cervicovaginal specimens taken at home. A novel collection device and medium were used for cervicovaginal sampling. Specimens were tested by three HPV DNA assays: hybrid capture 2 (HC2; Qiagen Corp., Gaithersburg, MD), Linear Array (LA; Roche Molecular Systems, Pleasanton, CA), and Amplicor (Roche Molecular Systems, Pleasanton, CA). Liquid-based cytology was performed on cervical specimens. We compared the overall positivity (a proxy for clinical specificity) for any carcinogenic HPV genotype and calculated the agreement across assay and specimen type using McNemar's test for differences in test positivity. Across all three assays there were no significant differences between clinician-collected and self-collected cervicovaginal specimens (P > 0.01 for all comparisons). For both cervicovaginal specimens (clinician collected and self-collected), fewer women tested positive by HC2 than by LA or Amplicor (P < 0.01 for all comparisons). HC2 had the best agreement between specimens for all assays. HC2 is likely more clinically specific, although possibly less sensitive, than either PCR test. Thus, use of HC2 on cervicovaginal specimens for screening could result in fewer referrals compared to LA and Amplicor.In the United States, annual cervical cancer incidence and related mortality have fallen to ϳ10,000 and ϳ4,000 per year, respectively (18). However, these reductions have not been uniformly achieved since more than half of all cervical cancer occurs in medically underserved populations (http://www.cdc .gov/cancer/cervical/), of which the Mississippi Delta region ranks highest (13). The Mississippi Delta region is one of the poorest areas in the United States, and it has been referred to as a "Third World country in the heart of America" (23). Overall, the rates of cervical cancer incidence and mortality in this region are some of the highest in the country and comparable to rates in some low-and middle-income countries (13).Cervical cancers in the United States arise from both lack of screening and lack of appropriate follow-up of abnormal results (10). Unfortunately, even in the United States, formidable barriers remain for cytology programs to successfully prevent cancer in underserved populations. Women must repeat screening through clinic visits throughout their adult life because cervical cytology is insensitive (21), and women who screen positive are often lost to follow-up (2,4,12). In order to reduce the excessive burden of cervical cancer in these medically underserved populations, novel a...