OBJECTIVES: The objective of this retrospective cohort study is to analyze the effect of the iPLEDGE program on rates of fetal exposure to isotretinoin in females of child-bearing potential (FCBP). METHODS: This study used databases from Kaiser Permanente Southern California, which includes prescription records, laboratory results, and outpatient/inpatient visit procedures and diagnoses. All FCBP who filled isotretinoin during the study period of March 1, 2004 to February 29, 2008 were identified.  Chart review was performed to validate pregnancy in patients with positive pregnancy indicators.  The analysis was performed at the treatment course-level.  Treatment courses were excluded if they straddled both before and after iPLEDGE implementation on March 1, 2006.  Poisson regression was used to analyze the impact of iPLEDGE on the rate of fetal exposures, controlling for age, prior utilization of acne prescription medications, and other risk factors. RESULTS: There were a total of 8 fetal exposures during 2585 treatment courses before iPLEDGE and 6 fetal exposures during 1595 treatment courses after iPLEDGE implementation.  Unadjusted fetal exposure rates increased slightly from 3.09 per 1000 treatment courses to 3.76 per 1000 treatment courses with iPLEDGE.  When controlling for other factors, the rate ratio for fetal exposure after compared to before iPLEDGE implementation was 0.45 [95%CI: 0.31, 0.67] in FCBP less than 21 years of age.  In FCBP greater than or equal to 21 years of age, the rate ratio was 1.46 [95%CI: 1.10, 1.94]. CONCLUSIONS: The risk of fetal exposure among treatment courses filled by younger FCBP significantly decreased by 55% after the implementation of iPLEDGE.  In contrast, the risk of fetal exposure significantly increased by 46% after iPLEDGE began among treatment courses filled by older FCBP.  Our results suggest that the iPLEDGE program had a differential effect on the rate of fetal exposures to isotretinoin depending on patient age group.