Spontaneous regression of cervical intraepithelial neoplasia grade 2 (CIN2) lesions has been recognized since 1955, but predictors of this are poorly understood. Among the predictive markers studied, p16(INK4a) has been suggested to be of some value in monitoring the diagnosis of CIN2. In this clinical trial, 90 Brazilian women, diagnosed to CIN2 and high-risk human papillomavirus infection, were randomized into two groups of equal size: 45 women whose lesions were excised and 45 women subjected to prospective follow-up at 3-month intervals at least for 1 year (mean 6.8 months). p16(INK4a) expression was analyzed in paraffin-embedded sections using immunohistochemical staining. Among the 45 women in the follow-up group, 42% experienced spontaneous regression, 11% showed persistence, 22% progressed to CIN3, and 20% had partial regression to CIN1 or ASCUS (atypical squamous cell undetermined signifiance). p16(INK4a) expression was detected in 68.9% of the patients. In univariate survival (Cox) analysis, no significant difference in regression was obtained between p16(INK4a)-negative and -positive CIN2 lesions (adjusted HR = 1.1; 95% CI 0.6-2.0). In conclusion, p16(INK4a) expression could be useful in the diagnosis of CIN2. However, it failed to predict the outcome of CIN2. Because of its high spontaneous regression rate, follow-up could be considered as a management option of CIN2 in young and compliant women.