In the prairie pothole region of North America, development of Indices of Biotic Integrity (IBIs) to detect anthropogenic impacts on wetlands has been hampered by naturally dynamic inter-annual climate fluctuations. Of multiple efforts to develop IBIs for prairie pothole wetlands, only one, the Index of Plant Community Integrity (IPCI), has reported success. We evaluated the IPCI and its ability to distinguish between natural and anthropogenic variation using plant community data collected from 16 wetlands over a 4-year-period. We found that under constant anthropogenic influence, IPCI metric scores and condition ratings varied annually in response to environmental variation driven primarily by natural climate variation. Artificially forcing wetlands that occur along continuous hydrologic gradients into a limited number of discrete classes (e.g., temporary, seasonal, and semi-permanent) further confounded the utility of IPCI metrics. Because IPCI scores vary significantly due to natural climate dynamics as well as human impacts, methodology must be developed that adequately partitions natural and anthropogenically induced variation along continuous hydrologic gradients. Until such methodology is developed, the use of the IPCI to evaluate prairie pothole wetlands creates potential for misdirected corrective or regulatory actions, impairment of natural wetland functional processes, and erosion of public confidence in the wetland sciences.