Quagga mussels (Dreissena bugensis) are considered one of the most deleterious invasive species in freshwater ecosystems because they can alter food webs by changing energy and nutrient flows. Generally, the predicted effect of quagga mussels on the trophic niche of co-occurring fish is a decrease in trophic level and a shift to use of more littoral-based energy, especially in pelagic-feeding fishes. We evaluate variation, in trophic niche of fishes in Lake Powell using stable isotopes to see if they conform to this expected pattern, and we compare current trophic niche of fishes to trophic niche measured prior to full colonization by quagga mussels. After colonization by quagga mussels in Lake Powell, trophic niche of all five fish species changed, but the direction and magnitude of change varied significantly between regions of the lake. In the southern region of the lake, some species exhibited a trend of decreasing δ15N, (i.e., decreased trophic level), and an enrichment of δ13C, indicating a littoral energy shift consistent with the expected effect of quagga mussels. However, in the northern region of the lake some species exhibited an increase in trophic position and a shift toward the pelagic energy pathway across the same time period. Regional differences in the lake, including extreme fluctuations in water level and high input of sediments from the Colorado River, may ameliorate the effect of quagga mussels.