White blood cell apoptosis has been demonstrated and is suspected to contribute to the decrease in peripheral leukocyte count and the severity of the disease during acute T. brucei infection in rats. Thus, an investigation of blood and tissue leukocyte apoptosis during T. brucei infections in two natural hosts (Red Sokoto (RS) and West African dwarf (WAD) goats (12 per group)), with differing levels of trypanosusceptibility was conducted. Nine out of 12 animals in each breed group were infected intraperitoneally with 104 parasites/mL and euthanized over time points. Blood and tissues were collected for detection and quantitation of apoptosis by three methods (DNA gel electrophoresis, light microscopy and transmission electron microscopy). T. brucei infected RS animals (trypanosusceptible) showed a significant increase in apoptosis of white blood cells (p=0.0092) and splenocytes (p=0.0239). The infected WAD animals (trypanotolerant) also showed a relatively lower but yet still significant (p=0.0022) increase in white blood cell apoptosis. Apart from the liver, significant increase (P<0.05) in tissue cell apoptosis was recorded in infected RS compared to non-infected controls. The mean white blood cell and splenocyte apoptosis was significantly higher (p=0.0072) in RS compared to WAD. In addition, the peak blood cell apoptosis tallied with peak parasitemia and anemia as well as with the lowest leukocyte count in RS animals. Our data support a relationship between peripheral and tissue white blood cell apoptosis and susceptibility to T. brucei infections. The molecular mechanisms mediating apoptosis of host cells during trypanosoma infections may reveal novel therapeutic or vaccine targets.