The association of breast density (% of breast volume involved by fibro-glandular densities) with the risk of interval cancer (IC) was investigated by reviewing a consecutive series of 346 cancers detected at screening (SDC) during 1996 -1999 and of 90 ICs, reported as negative in the same period and diagnosed in the following 2 years, and comparing them to a random sample of 360 healthy controls. The probability of IC was significantly associated with breast density, whatever grouping (0/ Multivariate analysis confirmed the independent association of breast density to IC, the highest risk being observed for 474% density class (OR vs 0% class ¼ 13.4, 95% CI 2.7 -65.6, OR vs all other density classes ¼ 5.1, 95% CI 2.6 -10.0). Age showed an independent association too, older women having a lower risk of IC (OR ¼ 0.52 95% CI 0.3 -09). Breast density (474%) resulted as being a major determinant of IC. Special screening protocols (shorter rescreening interval, routine use of ultrasonography) might be suggested for these subjects in order to improve screening sensitivity and efficacy. Mammographic screening is effective in reducing breast cancer mortality (Wald et al, 1993), although its sensitivity is not high. Based on interval cancer (IC) proportional incidence, biennal screening sensitivity has been estimated to be as low as 75% (Paci et al, 1990;Zappa et al, 2002). Thus, efforts should be made to reduce IC frequency, and determining the causes of screening faults is a baseline condition for further action.At retrospective review (Egan and Mosteller, 1977; Ciatto et al, 1995a, b), most ICs are classified as 'occult' or 'true interval', a relevant proportion as 'minimal sign' and a minority as 'screening error'. The corresponding frequencies determined for the Florence District Programme were 61.9, 26.1 and 11.9%, respectively (Ciatto et al, 1995a, b). Breast radiological density may have a masking effect on small cancer lesions; it is likely to be a determinant of false-negative mammography (Peeters et al, 1989), and might be associated with IC, particularly in cases reviewed as 'occult'. Other variables, such as age (Wald et al, 1993), use of single or double view (Bryan et al, 1995) and use of single or double reading (Ciatto et al, 1995a, b) have been shown to be associated with mammography sensitivity and might also be associated to IC.In Florence District, mammographic screening has been ongoing at the Centro per lo Studio e la Prevenzione Oncologica (CSPO) since 1970, being extended to Florence City in 1990.Screening efficacy has been demonstrated by means of a casecontrol study (Palli et al, 1986), and the proportional IC rate in women aged 50 -69 years has been reported to be 18% (95% CI 10 -24) and 42% (95% CI 29 -59) in the first or second year of the interval, respectively: the sensitivity of biennal screening, estimated on the basis of proportional IC incidence, was 75% (Paci et al, 1990).In the present study, a consecutive series of IC was compared to screen-detected cancers (SDC), and the associa...