Long-term trends in the response of benthic macrofauna to hydrological conditions were examined in the Lavaca-Colorado Estuary, Texas. Four stations representing a range of salinities in the Lavaca-Colorado Estuary were sampled quarterly for benthic macrofauna and hydrography from April 1988 to October 2008. The relationship between climate variability and local salinity patterns and benthic populations was investigated using the Oceanic Nino Index (ONI), North Atlantic Oscillation (NAO), and North Pacific Index (NPI). Mean salinity declined during the 20 yr study period. Observed changes in salinity were related to river discharge and the ONI because there were more El Nino events in the first half of the study period relative to the second half. Benthic macrofaunal abundance was significantly correlated with salinity, the ONI and the NAO, indicating that global climate variability and the resulting effects on local salinity patterns are important factors shaping benthic macrofaunal communities. There was no significant linear trend in temperature over time, and negative correlations between individual taxa and temperature were likely due to seasonality. While drivers other than physical hydrological factors can obviously affect benthic macrofaunal communities, strong connections between global climate signals, precipitation, and local salinity patterns provided the most plausible mechanistic connection between climatic variability and benthic macrofaunal response in the estuary. An increasingly unstable climate may lead to potentially strong effects in estuarine ecosystems because stability is known to affect diversity and productivity. The vulnerability of estuarine ecosystems to the effects of climate variability will be exacerbated as human population growth and water resource development continues to increase the demand for and stress on coastal and marine resources.