AbstractMetaplastic cells with nebular cytoplasmic changes in the cervical smear are classified in the Dutch coding system for cervical screening as KOPAC O8 cells. Since these nebulated cells are already documented by Papanicolaou, we refer to these cells as Papanicolaou's nebular cells.We examined the simultaneous presence of these characteristic metaplastic cells and high‐grade squamous intraepithelial lesion (HSIL) in a population‐based data base from January 1991 and December 1996.The odds ratio (OR) of nebular cells concurring with HSIL increases with age. For the age cohort 30 years, the OR was 7.8 with a 95% confidence interval (CI) of 4.4–13.9. For the age cohort 60 years, the OR was 35.3 with a 95% CI of 7.8–159.2. Aiming to determine the nature of these nebular metaplastic cells, we performed Chlamydia and HPV PCR on 587 and 1,483 smears, respectively. With an OR of 0.9 [0.3–2.4] it is unlikely that Chlamydia plays a role in the appearance of these nebular cells in the smear. This study shows that with an OR of 5.9 [1.7–21.3] HPV is not only related to large koilocytosis but also to a nebular change of small metaplastic cells.This study reports that nebular changes of small metaplastic cells are related to cervical cancer and to HPV infection. Diagn. Cytopathol. 2012. © 2010 Wiley Periodicals, Inc.