We have reported on a model in which MO ewes are fed 150% of NRC recommendations from 60 d before conception to term or fed only to requirements (CON). Offspring (F1) of MO ewes exhibit hyperphagia, increased weight gain and adiposity, and insulin resistance in response to an ad libitum feeding challenge when compared with CONF1 (J. Anim. Sci. 2010. 88:3546). We recently reported that male grandsons (MOF2) also experience a significant increase in body mass and insulin resistance in response to a similar bout of ad libitum feeding as 2 year old adults, demonstrating a multigenerational effect of MO grandmothers on their grandsons. To evaluate potential offspring sex differences, we studied the multigenerational impact of MO on the response of 2-year-old adult female F2 to a 12-week ad libitum feeding challenge, MOF2 (n = 6) or CONF2 (n = 6). A dual x-ray absorptiometry (DEXA) scan was performed before and after the feeding challenge to determine changes in % body fat and % lean. Body weights and plasma samples were obtained bi-weekly. Glucose was evaluated via a colorimetric assay and insulin was analyzed via a validated RIA. Data (M ± SEM) were analyzed using the mixed procedure in SAS. No differences in body weight, % body fat or % lean were observed for CONF2 and MOF2 females either before or after the feeding trial. By the end of the feeding trial, body weight and % body fat were markedly increased (P < 0.05) in both groups. Plasma glucose was greater (P < 0.05) in MOF2 than CONF2 females, while plasma insulin tended to be greater (P < 0.06) in MOF2 than CONF2 females throughout the trial, resulting in a markedly elevated (P < 0.01) HOMA-IR in MOF2 vs. CONF2 females (7.8 ± 0.7 vs. 5.0 ± 0.7, respectively) demonstrating severe IR in MOF2. These data demonstrate that as previously reported for male OBF2, an ad libitum feeding challenge during adulthood induced marked insulin resistance in female OBF2. In contrast to the male OBF2, however, this elevated insulin resistance developed in the total absence of any increase in weight gain over that of female CONF2 in response to ad libitum feeding.