In order to compare the prophylactic effect provided by a poly(D,L-lactide) sustained-release device (SRD) containing isometamidium (ISMM) with that provided by the classical intramuscular injection of the drug, a field trial was carried out at the Madina Diassa Ranch in Mali. One- to 3-year-old N'Dama cattle were randomly divided into three groups. The first group (n = 42) was treated with ISMM at a dose of 1 mg/kg of body weight, the second group (n = 44) received the same dose of the drug via an SRD, which was subcutaneously implanted in the shoulder region, and the third group (n = 36) was kept as an untreated control group. All animals were treated with diminazene aceturate (7 mg/kg of body weight) 2 weeks before the start of the experiment and were tested monthly by the buffy coat technique for a period of 8 months. Glossina morsitans submorsitans was the most important tsetse species, with apparent densities (number of catches/trap/day) varying between 11.9 and 38.7 over the experimental period. Eight months after treatment the cumulative infection rates were 27.7, 58.5, and 77.4% in the group with the SRD implant, the group receiving the intramuscular injection, and the control group, respectively. Statistical analysis showed that the incidence of trypanosomiasis was significantly lower (P = 0.006) in the group which received ISMM via the SRD than in the one which was treated with ISMM intramuscularly.