In addition to oncogenic 'high-risk' human papillomaviruses (HR-HPV), several co-factors are needed in cervical carcinogenesis, but it is poorly understood whether these HPV co-factors associated with incident cervical intraepithelial neoplasia (CIN) grade 1 are different from those required for progression to CIN2 and CIN3. To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV co-factors increasing the risk of incident CIN1, CIN2 and CIN3. Data from the New Independent States of the Former Soviet Union (NIS) Cohort (n = 3187) and the Latin American Screening (LAMS) Study (n = 12,114) were combined, and co-factors associated with progression to CIN1, CIN2 and CIN3 were analysed using multinomial logistic regression models with all covariates recorded at baseline. HR-HPV-positive women (n = 1105) represented a subcohort of all 1865 women prospectively followed up in both studies. Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2 and CIN3, respectively. Baseline HR-HPV was the single most powerful predictor of incident CIN1, CIN2 and CIN3. When controlled for residual HPV confounding by analysing HR-HPV-positive women only, the risk profiles of incident CIN1, CIN2 and CIN3 were unique. Completely different HPV co-factors were associated with progression to CIN1, CIN2 and CIN3 in univariate and multivariate analyses, irrespective of whether non-progression, CIN1 or CIN2 was used as the reference outcome. HPV co-factors associated with progression to CIN1, CIN2 and CIN3 display unique profiles, implicating genuine biological differences between the three CIN grades, which prompts us to re-visit the concept of combining CIN2 with CIN3 or CIN1.