OBJECTIVE: To report on our results using enhanced oocyte screening methods and to assess the value of such measures in a large oocyte donation program. DESIGN: Retrospective analysis at a university-based IVF center from 1997-2006. MATERIALS AND METHODS: After passing initial questionnaire screening, donor candidates were examined in accordance with ASRM guidelines, which included a health status questionnaire, on-site consultation and examination with a physician and psychologist, and the mandatory tests for infectious disease, drug use, and cystic fibrosis. Enhanced screening included: face to face consultations with a genetic counselor, the Minnesota Multiphasic Personality Inventory (MMPI), universal screening for Tay Sachs, Fragile X (as of 2005), and karyotypic abnormalities. Recipient husbands were tested in the case of Ashkanazi matches. RESULTS: Of 1,071 candidates presenting for on-site evaluation, 511 (48%) passed the screening process, of whom 474 (93%) donated. Twenty percent (n=212) of candidates withdrew their applications, and 560 (32%) failed screening. Candidates failed due to genetic factors (11%), psychological factors (10%), medical conditions (6%), infectious diseases (3%), and positive drug screens (2%). Of the 121 candidates rejected for genetic factors, 68 were for abnormal genetic testing and 53 for a personal/family history suggestive of a transmissible genetic trait, such as dyslexia, early cardiac disease, and aggressive cancers. There were 29 cystic fibrosis mutation carriers, and 12 abnormal hemoglobin electrophoresis patterns. Enhanced screening accounted for 21% of the genetic exclusions, with 9 Tay Sachs carriers, 6 inconclusive Tay Sachs results, 8 abnormal karyotypes, and 2 Fragile X carriers (intermediate range). Of the 112 candidates excluded for psychological factors, 24 had a personal history of a psychological disorder, 28 with unacceptable behavioral traits, and 44 with a family history of psychological disorders. Enhanced screening accounted for 14% of the psychological exclusions, as 16 had an elevated MMPI score. CONCLUSIONS: While enhanced oocyte donor screening uncovers a significant number of donors with potential problems, it also reduces the numbers of available donors. Programs may want to use the information presented here to determine if some or all of the elements of enhanced donor screening should be incorporated into their protocols.