Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases worldwide and a prime cause of cervical cancer. The HPV DNA is detected in approximately 80-90% of all cervical cancers, with HPV 16 and 18 being the high risk conferring human carcinogens. DNA damage and diminished DNA repair mechanisms are potential biological surrogates of HPV infection that warrant further research in different tissues and populations. Notably, we do not know the extent to which the high risk HPV 16 and 18 differentially affect cervical cells versus other systems such as peripheral blood lymphocytes (PBLs). We evaluated DNA damage and repair in women who tested positive for HPV 16 or HPV 18 and healthy control women without HPV 16 or HPV 18 infection. We found that the DNA damage as measured by the Comet assay was markedly greater in cervical cells of women with HPV 16 (mean: 8.1 as% DNA in tail, 95% CI: 7.6-8.7) or HPV 18 infection (mean: 9.6, 95% CI: 8.9-10.2) than controls (mean: 6.7, 95% CI: 6.2-7.4) (p<0.05). By contrast, in PBLs, we did not find a significant difference in DNA damage between women with HPV 16 or 18 infection versus controls, as measured by the Comet assay or the Conventional Chromosomal Aberration analysis (p>0.05). We observed, however, the DNA repair capacity, as measured by the X-ray induced challenge (XRC) assay, was significantly impaired in PBLs from women with HPV 16 or 18 infection compared to controls (p<0.05). This is the first comparative study, to the best of our knowledge, suggesting that the cervical swab cells might be better suited than peripheral lymphocytes as biosamples for detection of HPV 16 or 18 biological effects on DNA damage. In addition, these findings suggest that the Comet assay performed only in PBLs may potentially lead to false negative diagnosis of DNA damage. Taken together, these observations contribute to development of future diagnostic innovation and precision sampling strategies for robust detection of the biological effects of HPV 16 or 18 in women. We conclude by a brief discussion of implications for HPV clinical diagnostics and precision medicine innovation.