Blue crab, Callinectes sapidus, commercial landings in the USA have been declining at an alarming rate. In South Carolina, these declines are significantly correlated with years of decreased rainfall and elevated salt marsh salinity. Previous studies suggest that higher salinity increases the risk of infection by Hematodinium sp., a dinoflagellate parasite of blue crabs, C. sapidus. A 4-year survey (June 2008 to March 2012) of blue crabs in the ACE Basin National Estuarine Research Reserve documented (1) the temporal and spatial patterns of Hematodinium sp. infection in relation to salinity, (2) some environmental correlates of disease prevalence, and (3) the characteristics of infected blue crabs. Sampling was conducted four times a year in March, June, September, and December in the South Edisto, Ashepoo, and Combahee rivers beginning in June 2008. Crab hemolymph samples were collected and preserved and DNA was successfully amplified for 2,303 individuals. Hematodinium sp. infection was evaluated by PCR amplification of its 18S rRNA gene and adjacent regions. Prevalence was highest in December 2008 in the Combahee River at sites closest to St. Helena Sound. The spatial and temporal pattern of Hematodinium sp. infection was correlated with several environmental parameters. Infected crabs exhibited differences in carapace shape and body condition compared to uninfected crabs. Overall, these results suggest that blue crabs in regions of higher salinity are at greater risk of infection by Hematodinium sp. and infected individuals exhibit sub-lethal effects of the disease.