The field trial was conducted to assess the problem of trypanocidal drug resistance in Konso District using Diminazeneaceturate (Veriben®) and Isomethamedium chloride (Veridium®). A total of 250 naturally infected animals were screened and divided in to two groups of 125 animals. Group I was treated with Diminazeneaceturate at a dose of 3.5 mg/kg/ bodyweight (b.w.) and group II was treated with Isomethamedium chloride at a dose of 0.5 mg/kg/b.w. and monitored for relapses at 15 days interval for 90 days. The relapsing cases were treated with double dose of the drugs and monitored at the same interval for the same period.It was found that the proportion of relapsing cases was 51.2% and 32.81% in group I and 41.60% and 30.77% in group II after single and double doses of the drugs respectively. The relapses were due to T.congolense (75%) followed by T. vivax (20.31%) and T. brucei (4.65%); and T. congolense(86%) followed by T. vivax (9%) and T. brucei(5%) after single and double doses in group I respectively. similarly the relapses observed in group II were higher for T. congolense (71%) followed by T. vivax (27%) and T. brucei(2%) and T. congolense(56%) followed by T. vivax (38%) and T. brucei(6%) after single and double doses respectively. However, no statistically significant difference has been observed among different sexes (P>0.05) showing their equal susceptibility. The overall mean PCV of the infected animals was 24.34+0.27 with standard deviation (s.d) of 4.34 at 95% CI (23.80-24.88).Therefore, relapses were observed in both single and double doses of both drugs requiring integrated sustainable vector control, enhanced community awareness in the appropriate and strategic use of the drugs, and further research on multiple drug resistance to minimize further development of the problem.