This is the first large scale investigation of the epidemiology of Blastocystis hominis in the United States. Trends in annual, seasonal, geographical and host distribution and symptomology by age, sex and season are reported in 48 states and the District of Columbia in 2002-2004. Sixteen percent of 10,582 fecal specimens from 5,291 patients tested positive. Annual prevalence rate declined from 23% in 2000 to 11% in 2004. Infections were most prevalent in September and October and in coastal states. About one fifth of the infections were concurrent with 10 other parasitic species the most common of which was Cryptosporidium parvum. Females submitted about twice as many specimens as males and were markedly more frequently infected at the 40-49 years age group. Children (age 0-9 years) were the least frequently infected but the prevalence rate in male and female children was 15 and 6%, respectively. About two thirds of infected patients were symptomatic with highest frequency of symptoms observed between July and September. Intestinal symptoms were considerably more common than extra-intestinal symptoms especially in females. Diarrhea and fatigue were the most common symptoms in both male and females.