The treatment of mice with indomethacin lowered Trypanosoma brucei parasitemia 1 to 2 log10 because it quickly promoted the differentiation of rapidly dividing long, slender trypanosomes into short, stumpy forms that do not divide in the mammal but do develop a functional mitochondrion and the ability to infect the tsetse. Since natural resistance correlates with the rate of differentiation, this observation may provide important information about factors that control the severity of trypanosomiasis.