The newly introduced Bethesda System proposes to replace the terms dysplasia, carcinoma in situ (CIS), or cervical intraepithelial neoplasia (CIN) with two terms, low-grade squamous intraepithelial lesion (SIL) or high-grade SIL. We tested the biologic relevance of the Bethesda System (ie, its ability to establish a close correlation between biologic behavior and the different grades of lesions) in a series of 528 women with genital human papillomavirus (HPV)-associated precancerous lesions prospectively followed for 10 years. The cervical biopsies were reclassified as either low-grade or high-grade SIL, and the data obtained by colposcopy, Papanicolaou smear, and HPV typing, as well as the biological behavior of the lesions, were analyzed in these two groups. Altogether, 77.4% (376 of 486) of the lesions were classified as low-grade SIL lesions; the rest (22.6%) belonged to the high-grade SIL category. In the low-grade SIL category, 46.8% of the women were 24 years old or younger, as compared with 37.3% in the high-grade SIL group. The colposcopic appearance was normal significantly more frequently in the low-grade SIL lesions (22.1%) than in the high-grade category (8.5%) (P less than .001). A single Papanicolaou smear was inadequate to distinguish between low-grade and high-grade SIL, as evidenced by almost identical distributions of Papanicolaou smear class I and II cells in both categories. Noteworthy was the discovery of normal Papanicolaou smears in 8.2% of the high-grade SIL lesions.(ABSTRACT TRUNCATED AT 250 WORDS)