Pathogenesis of buffalo-pox virus (BP4 strain) in buffalo calves following intradermal inoculation revealed bimodal thermal reaction. The prominent symptoms were lacrimation, mucoprulent nasal discharge and diarrhoea. The typical pook lesions produced in the skin were passed through reseolar, papular, vesicular, pustular and desquamative stages of infection followed with a second rash, between day 6-8 on the lips, tongue, neck, perinium region and around the nostrils and eyes. After the eclipse phase of 10 hours, the concentration of the virus started increasing logarithmically. Thereafter, the virus was subsequently detected in the regional lymphnode, blood stream and central organs viz., lung, liver & spleen on 2nd, 4th and 5th day, respectively. In blood stream the virus was found to be associated with white blood cells. Secondary viremia was again on day 6 post-inoculation. Gross and microscopic changes were observed in these organs. The presence of virus along with pathologic changes were also detected in stomach and intestine. The disease ran a course of 13 to 15 days.