A change of continuation phase tuberculosis (TB) treatment regimen from ethambutol (E) and isoniazid (H) combination for 6 months (6EH) to rifampicin (R) and isoniazid (H) combination for 4 months (4RH) was recommended. However, the effect of the regimen switch in the Ethiopian setting is not known. A comparative cross-sectional study among 790 randomly selected new cases of TB (395 each treated with 4RH and 6EH during the continuation phase) was conducted in nine health centers and one hospital in three zones in southwestern Ethiopia. The switch of continuation phase TB treatment regimen from 6EH to 4RH has brought better treatment outcomes which imply applicability of the recommendation in high prevalent and resource constrained settings. Therefore, it should be maintained and augmented through further studies on its impact among the older, rural residents and HIV positives.