A case-control study of 525 histologically confirmed cases of cervical intraepithelial neoplasia grade III and 512 controls was done in Spain and Colombia to assess the role of various risk factors taking into account the effect of human papillomavirus (HPV). The presence of HPV DNA, assessed by a polymerase chain reaction-based method, was the strongest risk factor identified. In Spain the adjusted odds ratio (OR) and 95% confidence interval (CI) (numbers in parentheses) were 56.9 (24.8-130.6) and, in Colombia, were 15.5 (8.2-29.4). In addition to HPV, the multivariate analysis revealed independent effects of early age at first intercourse (in Spain ORa, 4.3; 95% CI, 2.0-9.3 for ages < 17 versus 20+ years and in Colombia ORa, 9.0; 95% CI, 2.6-30.9 for ages < 14 versus 20+ years), and antibodies to Chlamydia trachomatis (in Spain ORa, 2.3; 95% CI, 1.1-4.5; and in Colombia ORa, 1.7; 95% CI, 1.1-2.7). High parity showed a significant effect only in Colombia (ORa, 2.0; 95% CI, 1.0-5.0 for > or = 6 versus 1) while number of partners of the woman and specially of her husband showed a strong effect in Spain only (ORa, 6.9; 95% CI, 3.1-15.3 for partners of the husband > or = 21 versus 1-5). Smoking and use of oral contraceptives did not show significant or consistent associations. Among HPV-DNA positive women early age at first intercourse and high parity increased the risk of cervical intraepithelial neoplasia III but the effect was statistically significant only for the former.(ABSTRACT TRUNCATED AT 250 WORDS)