Interindividual variation in the composition of the human gut microbiome was examined in relation to demographic and anthropometric traits, and to changes in dietary saturated fat intake and protein source. One hundred nine healthy men and women aged 21 to 65, with BMIs of 18 to 36, were randomized, after a two-week baseline diet, to high (15% total energy [E])- or low (7%E)-saturated-fat groups and randomly received three diets (four weeks each) in which the protein source (25%E) was mainly red meat (beef, pork) (12%E), white meat (chicken, turkey) (12%E), and nonmeat sources (nuts, beans, soy) (16%E). Taxonomic characterization using 16S ribosomal DNA was performed on fecal samples collected at each diet completion. Interindividual differences in age, body fat (%), height, ethnicity, sex, and alpha diversity (Shannon) were all significant factors, and most samples clustered by participant in the PCoA ordination. The dietary interventions did not significantly alter the overall microbiome community in ordination space, but there was an effect on taxon abundance levels. Saturated fat had a greater effect than protein source on taxon differential abundance, but protein source had a significant effect once the fat influence was removed. Higher alpha diversity predicted lower beta diversity between the experimental and baseline diets, indicating greater resistance to change in people with higher microbiome diversity. Our results suggest that interindividual differences outweighed the influence of these specific dietary changes on the microbiome and that moderate changes in saturated fat level and protein source correspond to modest changes in the microbiome.IMPORTANCE The microbiome has proven to influence health and disease, but how combinations of external factors affect the microbiome is relatively unknown. Diet can cause changes, but this is usually achieved by altering macronutrient ratios and has not focused on dietary protein source or saturated fat intake levels. In addition, each individual's unique microbiome profile can be an important factor during studies, and it has even been shown to affect therapeutic outcomes. We show here that the effects of individual differences outweighed the effect of experimental diets and that protein source is less influential than saturated fat level. This suggests that fat and protein composition, separate from macronutrient ratio and carbohydrate composition, is an important consideration in dietary studies.