To study the interaction between the levels of protein and fiber on the productive performance and health status of piglets, ninety-six 35-d-old piglets (9.11 +/- 0.60 kg of BW) were placed in 32 pens of 3 animals each and allotted to 4 dietary treatments for 21 d. The 4 diets were based on rice, dairy products, and soybean meal in a 2 x 2 factorial arrangement of treatments, with 2 levels of CP (15.4 vs. 19.4%, as-fed basis) and 2 levels of dietary fiber [DF; low fiber (LF) 5.3% NDF and high fiber (HF) 7.15% NDF, as-fed basis]. The HF diet was developed by supplementing the basal diet with 40 g/kg of wheat bran and 20 g/kg of sugar beet pulp. Animal performance was obtained weekly with samples of feces collected for microbiology on the first and the last experimental day and scored from 1 (liquid) to 4 (hard). On the last day, 1 pig from each pen was sampled for blood analyses of the acute-phase protein, major acute-phase protein of pigs (PigMap) and subsequently killed to register the digestive tract weight (including contents) and colon histology. Pigs fed the HF diets had greater ADG (390 vs. 457 g; P < or = 0.001) and large intestine weight (4.4 vs. 5.4% of BW; P < or = 0.05). This coincided with a greater (P < or = 0.05) short-chain fatty acid concentration (especially of acetic and butyric acids), a decrease in Escherichia coli counts (7.77 vs. 6.86 log of cfu/g of feces, P < or = 0.05), and an increase in the ratio of lactobacilli:enterobacteria (0.76 vs. 1.37, P < or = 0.05). However, CP level did not modify the productive performance, but 20% CP increased P < or = 0.05) the relative weight (% of BW) of the small (6.5 vs. 7.7) and large intestine (3.8 vs. 4.3). In the large bowel, the 20% CP diet increased the numbers of goblet cells (4.6 vs. 5.4/100 microm; P < or = 0.05) and reduced the numbers of intraepithelial lymphocytes (1.8 vs. 1.3/100 microm; P < or = 0.05). In relation to health status, increasing DF was dependent of the dietary CP content. Supplementing the 16% CP diet with DF reduced the fecal score and increased the antibiotics interventions, whereas the opposite was the case in the 20% CP diet. Pigs fed the 20% CP diet showed decreased (P < or = 0.05) PigMap concentrations than pigs fed 16% CP diets. As a whole, CP showed major effects on the gastrointestinal weight and gut barrier integrity, whereas DF increased the productive performance and promoted major changes in the microbial colonization and fermentation variables.