Granivorous desert rodents of the family Heteromyidae forage nonrandomly among “microhabitats” that vary in substrate, seed densities, and seed species composition. To explore the hypothesis that microhabitat use is sensitive to seed patch profitability, we quantified effects of seed size (1.96 vs. 5.21 mg/seed) and density (0.4–10.6 seeds/cm2) on Dipodomys deserti harvest rates, which is a measure of profitability when expressed as mg of seed taken per min. By manipulating seed density, we created large-seed and small-seed patches of known relative profitability and exposed D. deserti individuals to pairwise choices in the laboratory and field. We used three treatment classes: 1) large-seed patches that were more profitable than small-seed patches (equal seed densities); 2) large-seed and small-seed patches that were equally profitable (small-seed densities somewhat higher): and 3) large-seed patches that were less profitable than small-seed patches (small-seed densities much higher). Harvest rate increased nearly linearly with seed density, and profitability of large-seed patches was greater than small-seed patches of the same density. Cumulative harvest from a patch increased linearly with residence time up to a plateau; this “gain curve” indicates that animals move systematically within patches and hence avoid resampling already depleted areas. In the laboratory, animals visited small-seed patches first more often and visited them more frequently when they were more profitable than large-seed patches. When large-seed patches were of greater or equal profitability, large-seed patches were preferred by both measures. The expressed preference for large-seed patches, when animals were presented with equally profitable patches, suggests an underlying preference for large seeds. In the field, animals depleted all patches to a constant low profitability, in accord with qualitative predictions of optimal patch use models. These results suggest that patch preferences by D. deserti are affected by the economics of seed harvest.