Although eutrophication in the northern Gulf of Mexico contributes to the high fisheries productivity characteristic of the region, nutrient over-enrichment leads to the seasonal formation of hypoxic (≤ 2 mg L − 1 O 2) bottom water along the Louisiana–Texas continental shelf. Despite an increase in the magnitude and duration of hypoxic episodes in recent decades, fisheries landings have remained stable; nevertheless, hypoxia remains a threat to the long-term sustainability of regional fisheries production. The greatest threat to mobile nekton is likely to be the influence of reduced dissolved oxygen concentrations on habitat quality that potentially forces individuals and/or prey from generally favorable habitats. We examined patterns of habitat use by several flatfishes, taxa likely to be especially sensitive to the effects of bottom hypoxia, to unravel the potential influence of hypoxia using data collected during SEAMAP groundfish surveys from 1987 to 2000. Habitat suitability analyses indicated that most flatfishes examined selected a restricted range of suitable depths, temperatures, and salinities. Hypoxic environments were generally avoided by most flatfishes, indicating that hypoxia is likely to render large areas of the Gulf of Mexico unsuitable. In comparisons of spatial habitat suitabilities between years of moderate (areal extent of hypoxia < 12,500 km 2) and severe hypoxia (areal extent of hypoxia > 15,500 km 2), most flatfishes reflected a reduction in the suitability of areas immediately west of the Mississippi River and a concomitant increase in suitability within adjacent areas, although this pattern was not universal. Altered spatial distributions generally corresponded to species-specific suitabilities along depth, temperature, and salinity gradients, indicating that habitat suitability analyses may effectively predict population-level responses to hypoxia. Effects attributable to severe hypoxia persisted into fall, indicating that hypoxic episodes likely result in lingering effects to flatfish populations.