Rabies is a worldwide problem, and the case is most severe in developing countries where cellrnculture derived anti-rabies vaccines are unaffordable or the available nervous tissue-derivedrnvaccines are of questionable immunogenicity and may cause neurological complications. Thernaim of this research was to study pathogenicity and cross protection of local rabies virus isolatesrnwith Evenyl Roktincki Abelseth (ERA) based cell culture anti-rabies vaccine produced inrnEthiopia. The viruses were isolated from rabid dogsâ€™ brains and human saliva, and adapted onrnSwiss albino mice brain and cell lines. By titration, a minimum of 106.5TCID50/ml (in vitro) andrn104.5MICLD50/0.03ml (in vivo) virus titer were obtained. For pathogenicity study, mice wererninoculated intramuscularly with 250MICLD50/0.1ml of each adapted virus isolate and observedrnfor 45 days. Only two virus isolates, human origin sululta (HOS) and dog origin (DO) causedrn12.5% death. Cross protection of local isolates with ERA vaccinal strain was studied by in vivornand in vitro methods. For in vivo method, a group of mice were immunized on day zero andrnseven with 0.5ml (1:5 dilutions) of ERA based cell culture anti-rabies vaccine produced locally.rnOn day fourteenth, mice were challenged with working dilution of each local isolate and onerngroup with challenge virus standard (CVS-11), and observed for further 14 days. Based on thernsurvival rate, high protection was recorded in CVS-11 challenged mice and low protection in allrnisolates; protection to HOS challenged mice was very low. In vitro test was done by fluorescentrnantibody virus neutralization (FAVN) test on BHK-21 cell lines. Sera from dog immunized withrnlocally produced vaccine and OIE standard serum were incubated with working dilution of localrnvirus isolates and CVS-11 for 48 hours in the presence of cell lines. Maximum antibody titerrn(2.74IU/ml) was obtained with CVS-11 challenge virus and minimum antibody titer (1.55IU/ml)rnwas obtained with cow origin (CO) virus isolate. All locally isolated rabies virus show lowrnantibody titer when compared to CVS-11 and PV-12. From the results of this study, it can bernconcluded that local isolates have some genetic variation from fixed virus strain which can affectrnefficacy of the candidate vaccine and potency value should be set in-terms of local virus isolatesrnas challenge virus. Generally, the exact genetic relationship should be studied by molecularrntechniques and canine anti-rabies vaccine should be developed from locally isolated virus.rnKey Words: Cell Culture Vaccine, Cross protection, Local Isolate, Pathogenicity, Rabies