Our objectives were to evaluate the effectiveness of cervical cancer screening outside organized programs in the prevention of cervical carcinoma in situ (CIS) and to enhance the way in which case control studies avoid some common biases. In our case-control study, we assessed all incident, histologically verified cases of CIS registered from 1987 to 1997 in the population-based cancer registry of C te-d'Or, France (N = 104) and 208 controls randomly selected from the screened population and matched for age, date of last screening, residence, and pathology laboratory results. We considered as appropriate for controls screened women who had had at least one Papanicolaou smear in the 3 years preceding the diagnosis or similar period. Screening for controls was higher (67.8%) than for cases (41.4%; P < .001), with a relative protection against CIS of 3.09 (95% confidence interval, 1.83-5.22) and a prevented fraction in the screened population of 45% to 50%. These findings suggest a protective advantage for CIS even in the absence of organized screening. The methodologic approach has advantages as compared to previous types of case-control studies. Although further refinements still are warranted, learning about the protective effect of screening for CIS provides information that may be useful in assessing the impact of a screening policy on women actually at risk of invasive cervical cancer.