Among Piman and San Carlos Apache Indians, the rates of disseminated disease and death from coccidioidomycosis have declined 67 percent (p less than 0.001) and 71 percent (p less than 0.01), respectively, between the first and second half of a 22-year observation period (1959-1980), despite a lack of significant change in the rate of primary infection (as determined by the coccidioidin skin test) between the two 11-year periods. The two tribal groups studied comprised 76 percent of the Indian population in the endemic area. More than 90 percent of Pimans and San Carlos Apaches have full Indian heritage, and almost all of them have been lifelong inhabitants of the endemic region. There is no evidence that genetic factors are responsible for the Indians' decrease in mortality and mortality from disseminated coccidioidomycosis. Improvements in housing and working conditions appear to have lessened the exposure to dust laden with C immitis, decreased the size of infecting inoculum, and, thereby, contributed to a decline in disseminated coccidiodomycosis among these native Americans, who have often been considered to have increased susceptibility to this fungal infection. Thus, the outcome of coccidioidal infection in American Indians seems to be largely determined by environmental influences. The possibility of decreasing disseminated disease rates by reducing the inhalation of arthroconidia also has important implications for other ethnic groups.