ABSTRACT   Lumpy Skin disease (LSD) is an infectious viral disease of cattle caused by Lumpy Skin disease virus (LSDV) of the family Poxviridae characterized by skin nodules covering all parts of the body. There are many aspects of LSD remaining unknown, thus immunological, hematological and biochemical parameters were estimated. During an outbreak of LSD in Ismailia governorate in Egypt, 131 Friesian cattle aging (2-4 years) were examined clinically for the presence of LSD lesions during the period from July to November 2016. Twenty five from them showed lesions suspected to be LSD. The animals were feverish, had multiple skin nodules and enlargement of superficial lymph nodes typical of LSD. Case history details such as changes in management and diet, previous drug administration, clinical findings and method of treatment were recorded. LSD revealed a macrocytic hypochromic anemia and granulocytic leucocytosis. Biochemical analysis revealed hypoproteinemia, hypoalbuminemia and hypoglobulinemia but raises in gamma globulins. Significant increase in serum alanine aminotransferase, aspartate aminotransferase activities, creatinine level and blood urea nitrogen was recorded. All these alterations showed improvement after medication. Rapid and accurate diagnosis of Lumpy Skin disease (LSD) is very important for its control. In this study, laboratory diagnosis of LSD was done by using polymerase chain reaction (PCR), isolation in specific pathogen free, embryonated chicken eggs (SPF-ECE) via chorioallantoic membrane (CAM)route, identification of the isolates with ager gel precipitation test (AGPT) as well as detection of neutralizing antibodies in paired serum samples.In conclusion, our study supports the use of PCR as a sensitive and rapid method for LSD diagnosis in addition to isolation in SPF-ECE and identification of isolates with AGPT. Moreover, serum neutralization test (SNT) must be used for measuring neutralizing antibodies in paired serum samples as a confirmatory aid for serological diagnosis. Sequencing for PCR product was recommended specially for samples negative in isolation.