The South Carolina Department of Health and Environmental Control has collected, processed, and analyzed fish tissue total mercury (Hg) since 1976. For this study, skin-on-filet data from 1993 to 2007 were examined to determine biotic, spatial and temporal trends in tissue Hg levels for SC fishes. Because of the relatively high number of tissue Hg values below the analytical detection limits interval censored regression and censored least absolute deviations were used to construct several models to characterize trends. Large pelagic, piscivorous fish species, such as bowfin (Amia calva Linnaeus 1766), had higher levels of tissue Hg than smaller omnivorous species. Estuarine species had relatively low levels of tissue Hg compared to freshwater species, while two large open ocean species, king mackerel (Scomberomorus cavalla Cuvier 1829) and swordfish (Xiphias gladius Linnaeus 1758), had higher tissue Hg readings. For a given fish species, length was an important predictor of tissue Hg with larger individuals having higher levels than smaller individuals. The USEPA Level III ecoregion and water body type from where the fishes were collected were important in predicting the levels of tissue Hg. The Middle Atlantic Coastal Plain ecoregion had fishes with the highest levels of tissue Hg, while the Piedmont and Southern Coastal Plain ecoregions had the lowest. For a given ecoregion, large reservoirs and regulated rivers had fish with lower levels of tissue Hg than unregulated rivers. For reservoirs, the size of the impoundment was a significant predictor of tissue mercury with small reservoirs having higher levels of tissue mercury than large reservoirs. Landuse and water chemistry accounted for differences seen in fish of various ecoregions and waterbody types. Sampling locations associated with a high percentage of wetland area had fish with high levels of tissue Hg. Correlation analysis showed a strong positive relationship between tissue Hg levels and water column iron, total organic carbon, ammonia, and total kjedahl nitrogen, and a negative relationship with alkalinity, dissolved oxygen and pH. Results from principle component analysis revealed patterns between waterbody type and water chemistry variables that suggests hydrologic modification can have profound effects on the levels of fish tissue Hg in riverine systems. From 1993 to 2007, fish tissue Hg levels have trended lower. A spike in tissue Hg levels was observed in 2003-2005. The drying and rewetting of the landscape after the 2002 drought is hypothesized to have caused an increase in the methylation efficiencies of the system.