Azithromycin and diminazene aceturate combination therapy in experimental multidrug-resistant Trypanosoma brucei brucei infection in albino rats was evaluated. A total of forty-five female albino rats were used. These rats were randomly assigned to nine groups of five rats each. Group 1 was the uninfected-untreated group while groups 2 - 6 were infected with 1 × 106 trypanosomes suspended in 0.3 ml of normal saline intraperitoneally. Following infection and parasitaemia, group 2 was untreated while group 3 was treated once with 7 mg/kg diminazene aceturate. Groups 4 - 6 were treated with 10, 20 and 30 mg/kg azithromycin respectively for 7 days. Groups 7 - 9 were treated with combination of 7 mg/kg diminazene aceturate (DA) once and 10, 20 and 30 mg/kg azithromycin (AZT) respectively for 7 days. Level of parasitaemia, haematological indices (packed cell volume, total erythrocyte count, total leukocyte count, haemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration), survivability, body weight and rectal temperature were used to assess the effectiveness of the combination therapy. A significant reduction in parasitaemia levels was observed in the DA-treated group and AZT-treated group 6 while clearance of parasitaemia was observed in the DA-AZT treated groups 7 - 9 for periods between 1 and 5 days post treatment. The haematological indices and survivability of the DA-AZT treated groups were better than the DA-treated group despite the relapse recorded in those groups. One rat each in the DA-AZT combination groups survived till the end of the experiment. In conclusion, the DA-AZT combination treatment can be used as a possible adjunct to DA in the treatment of multidrug-resistant T. brucei brucei. The combination also enhanced survivability and decreased the effect of the disease in rats.