Background: An early detection of precursor lesions of cervical cancer will help to eliminate the worldwide burden of cervical cancer. Methods: This exploratory study aimed to identify, by matrix-assisted laser desorption/ ionization (MALDI) time-of-fight (TOF) mass spectrometry (MS), serum protein profles that distinguish cervical intraepithelial neoplasia grades CIN 1 or lower (#CIN 1) from CIN 2+ among 127 women infected with human papillomavirus (HPV) 16. Of these 127 women, 25 and 23 were diagnosed with CIN 2 or CIN 3, respectively (cases), and 79 were diagnosed with #CIN 1 (non-cases). Serum protein profles were generated by MALDI-TOF-MS. A total of 95 m/z peaks were tested for association with case status by two racial groups, African American (AAs) and Caucasian American (CAs). Results: Overall, 2 protein peaks identifed by our study demonstrated higher specifcity for identifying CIN 2+ than previously published studies. An increasing intensity of [m/z 4459] was associated with a higher risk of being a case, regardless of race with a specifcity of 58% for CIN 2 and a specifcity of 75% for CIN 3. An increasing intensity of [m/z 4154] was not only associated with a higher risk of being a case only among CAs, but also had an opposite effect among AAs. Conclusion: Identifcation of specifc proteins associated with the peaks detected in serum and development of antibody-based tests such as ELISA should lead to the development of race-specifc, non-invasive and cost effective screening tests with higher specifcity for identifying HPV 16 associated CIN 2+. © 2011 Schindler, publisher and licensee Dove Medical Press Ltd.