Women with a family history of ovarian cancer represent a high-risk group for the development of epithelial ovarian cancer. From July 1990 through December 1992, 386 women with a first-degree or multiple second-degree relatives with confirmed ovarian cancer were enrolled in a study to assess the utility of screening with transvaginal sonography, color flow doppler, and CA125. The mean age of the group was 41; 85% were premenopausal and 89/384 (23%) had 2 or more relatives with ovarian cancer. An initial ultrasound examination was abnormal in 89/384 (23%), 89% of whom were premenopausal. A persistent ovarian mass was detected in 15 patients and all were surgically proven to be benign. Mean CA125 levels were significantly higher and more variable in pre- vs postmenopausal women. CA125 was > or = 35 U/ml in 42/386 (11%) (36-232 U/ml). All but one of these women were premenopausal and 50% subsequently normalized. Two patients who were surgically explored for a rising CA125 had normal ovaries. An additional 19 patients have undergone prophylactic oophorectomy with no consistent histopathologic abnormality identified. These data demonstrate the difficulty inherent in screening a predominantly premenopausal population and do not clearly establish the efficacy of these modalities in the early detection of ovarian cancer.