The female kidney tends to be smaller, have a lower glomerular filtration rate, and be less susceptible to glomerulosclerosis than the male kidney. Insulin-like growth factor-I (IGF-I) is a peptide growth factor that appears to be important for normal and adaptive kidney growth. The purpose of this study was to compare the kidney growth response of the male and female rat kidneys to increased dietary protein intake and to see whether differences in IGF-I production or receptor expression might underlie any gender differences seen. Male (M) and female (F) Munich-Wistar rats (6 to 9 weeks of age) were randomized to isocaloric diets containing either 20% (NP) or 50% (HP) protein and studied after 3 and 14 days. In the male rat, wet kidney weight was significantly increased with HP at both day 3 (M-HP 1028 ± 21 mg vs M-NP 891 ± 19 mg, p < 0.01) and day 14 (M-HP 1499± 41 mg vs M-NP 1246 ± 37 mg, p < 0.01). In contrast in the female rat, while there was evidence of initial increased growth at day 3 in the kidneys of F rats fed HP (F-HP 788 ± 39 mg vs F-NP 650 ± 23 mg, p < 0.01), this difference was not sustained at 14 days (F-HP 961 ± 67 mg vs F-NP 931 ± 71 mg,p = NS). At day 3, kidneys of both male and female rats fed HP exhibited an increase in total protein but not DNA content. The kidneys of male rats showed increased protein/DNA ratios in the medulla and inner cortex, whereas in the kidneys of female rats, the increase in protein/DNA ratio was confined to the cortex. After 14 days of HP ingestion, the kidneys of male rats showed increases in total kidney content of both DNA and protein, and protein/DNA ratios returned to control values in whole kidney, inner cortex, and medulla. In contrast, in the kidneys of female rats, not only was overall growth response reduced, but neither total kidney protein content nor DNA content was increased. Increased protein/DNA ratios were seen in inner cortex and in outer and inner medulla, similar to that seen at day 3 in the kidneys of male rats. Neither baseline plasma (M-NP 793 ± 10 ng/ml, F-NP 704 ± 32 ng/ml, p = NS) nor kidney IGF-I content (M-NP 520 ± 55 ng/gm tissue, F-NP 506 ± 54 ng/gm tissue, p = NS) differed between male and female rats fed NP diets. Both male and female rats showed a comparable increase in kidney IGF-I after 3 days of HP ingestion, and kidney IGF-I returned to control values by 14 days. There was no significant difference in the number or affinity of glomerular IGF-I receptors between male and female rats. In conclusion, we have shown that in the adult male rat, an increase in dietary protein ingestion results in a sustained increase in kidney size that is initially consistent with a hypertrophic response but subsequently shows elements of hyperplasia. In contrast, in the female rat, although there was evidence of the initial hypertrophic (and IGF-I) responses to increased dietary protein, the increase in kidney size was not sustained. However, these profound gender-based differences in the growth response to dietary protein did not appear to be due to differences in kidney expression of IGF-I or its receptors.