Cell-mediated immune responses have been thought to be important in the control of human papillomavirus (HPV) infections. We examined cell-mediated immune responses to HPV-16 E6 and E7 in the peripheral blood using interferon gamma (IFN-gamma) enzyme-linked immunospot assay (Cellular Technology Ltd, Cleveland, Ohio) in women with HPV-16 infection who showed clearance and compared these women to women with HPV-16 persistence. Women participating in a longitudinal study of cervical HPV were recruited once cervical HPV-16 infection was detected by polymerase chain reaction. Four groups of women were examined: (1) persistent, (2) intermittent, (3) transient, and (4) cleared. Ninety-six samples from 55 women were compared. Comparing IFN-gamma enzyme-linked immunospot to the HPV-16 clearance of 10 women with recent persistence, none had response to either E6 or E7; of 24 women with recent clearance, 14 had E6 and 8 had E7 response. Women with intermittent persistence behaved similarly to the clearance group than recent persistors: 50% were positive to E6 and 20% to E7. In summary, anti-E6 responses seem critical in the immediate control of HPV, and in some women, an immune tolerance eventually develops if HPV is not eliminated soon after infection.