Interest by land-management and regulatory agencies in using biological indicators to detect wetland degradation, coupled with ongoing use of this approach to assess water quality in streams, led to the desire to develop and evaluate an Index of Biotic Integrity (IBI) for wetlands that could be used to categorize the level of degradation. We undertook this challenge with data from coastal wetlands of the Great Lakes, which have been degraded by a variety of human disturbances. We studied six barrier beach wetlands in western Lake Superior, six drowned-river-mouth wetlands along the eastern shore of Lake Michigan, and six open shoreline wetlands in Saginaw Bay of Lake Huron. Plant, fish, and invertebrate communities were sampled in each wetland. The resulting data were assessed in various forms against gradients of human disturbance to identify potential metrics that could be used in IBI development. Our results suggested that the metrics proposed as potential components of an IBI for barrier beach wetlands of Lake Superior held promise. The metrics for Lake Michigan drowned-river-mouth wetlands were inconsistent in identifying gradients of disturbance; those for Lake Huron open embayment wetlands were yet more inconsistent. Despite the potential displayed by the Lake Superior results within the year sampled, we concluded that an IBI for use in Great Lakes wetlands would not be valid unless separate scoring ranges were derived for each of several sequences of water-level histories. Variability in lake levels from year to year can produce variability in data and affect the reproducibility of data collected, primarily due to extreme changes in plant communities and the faunal habitat they provide. Substantially different results could be obtained in the same wetland in different years as a result of the response to lake-level change, with no change in the level of human disturbance. Additional problems included limited numbers of comparable sites, potential lack of undisturbed reference sites, and variable effects of different disturbance types. We also evaluated our conclusions with respect to hydrologic variability and other major natural disturbances affecting wetlands in other regions. We concluded that after segregation of wetland types by geographic, geomorphic, and hydrologic features, a functional IBI may be possible for wetlands with relatively stable hydrology. However, an IBI for wetlands with unpredictable yet recurring influences of climate-induced, long-term high water periods, droughts, or drought-related fires or weather-related catastrophic floods or high winds (hurricanes) would also require differing scales of measurement for years that differ in the length of time since the last major natural disturbance. A site-specific, detailed ecological analysis of biological indicators may indeed be of value in determining the quality or status of wetlands, but we recommend that IBI scores not be used unless the scoring ranges are calibrated for the specific hydrologic history pre-dating any sampling year.