This study aimed to investigate the potential causes of the summer mortality syndrome affecting the earthen pond cultured Nile tilapia, Oreochromis niloticus in some Egyptian farms. A total of 100 moribund O. niloticus showing non-specific clinical signs of septicemia and mortality (30- 65%) were collected from five farms at Tolombat 7, Kafr El-Sheikh, Egypt, during June 2019. All the fish farms share the same water source and perform some bad management practices. Inadequate water quality measures were noticed in all the investigated farms. Molecular detection of tilapia lake virus (TiLV) using PCR confirmed the non-existence of the TiLV in all examined specimens. A total of 19 pathogenic bacterial isolates were obtained from moribund O. niloticus: Streptococcus agalactiae (14), Aeromonas hydrophila (3), and Vibrio cholera (2). The predominance of Streptococcus agalactiae infections points to its intense involvement in such mortalities. S. agalactiae was confirmed by 16s rRNA gene sequencing and phylogenetic analysis. The PCR detection of virulence genes showed the existence of Hyl, cylE, scpB and camp < /em> genes in all S. agalactiae strains. Isolates of S. agalactiae showed variable susceptibility to the tested antibiotics with high resistance against ampicillin, amoxicillin and gentamycin. Infections were associated with several pathological alterations in naturally infected fish. The pathogenicity of S. agalactiae was confirmed in O. niloticus (90 % cumulative mortality). The data in the present study proved that the tilapia summer mortality syndrome is multifactorial. Thus, good managemental practices and water quality measures are recommended to minimize fish mortality.