The present study aimed to evaluate the effects of a post-weaning high-fat (HF) diet upon hepatic morphology in rats subjected to perinatal protein restriction. Pregnant Wistar rats were assigned to a normal-protein diet (NP; with 19 % of protein) or a low-protein (LP) diet (with 5 % of protein). At weaning, the following groups were formed: NP and NP-HF, males and females, which were fed standard chow and an HF diet, respectively. Likewise, LP rat dams originated LP and LP-HF offspring, both sexes. Euthanasia was performed at 6 months of age. Three-way ANOVA disclosed a three-factor interaction among sex, perinatal diet and HF diet in relation to body mass, retroperitoneal fat pad, liver mass:tibia length ratio, binucleation rate and hepatocyte area at 6 months old (P < 0·05). The high-fat diet intensified the effects of perinatal protein restriction concerning systolic blood pressure, genital fat pad and hepatocyte number (P < 0·05; two-way ANOVA). Furthermore, higher steatosis rates and insulin and leptin concentrations were found in males fed on the HF diet, indicating a sex–post-weaning diet interaction (P < 0·05; two-way ANOVA). Fetal programming and HF diet as a single stimulus caused mild hypertension at 3 months, an important reduction in hepatocyte number as well as stage 1 steatosis at 6 months. However, hypertension and hepatocyte number deficit were worsened and grade 2 steatosis occurred after exposure to the HF diet. All of these serve to highlight the paramount importance of intra-uterine conditions and postnatal diet quality when it comes to the pathogenesis of chronic diseases.