Epididymo-orchitis (EO) is a rare condition in the neonatal period. An underlying uropathy is variably associated with EO in published cases and more frequently seen in older children. In this case report, a male baby born at 26 weeks gestation had confirmed congenital Escherichia coli septicemia. The E. coli was sensitive to gentamicin, and he was treated with 10 days of intravenous gentamicin and cefotaxime, with normalization of markers of infection. He did not have a urinary catheter at any stage. He developed recurrent E. coli septicemia 19 days after ceasing antibiotics, in association with a tender scrotal swelling. A urine culture could not be obtained prior to commencing intravenous antibiotics. Surgical exploration revealed a right pyocele and a viable right testis. He was treated with 2 weeks of intravenous piperacillin and tazobactam and a further 2 weeks of oral amoxycillin and clavulanic acid. Urological investigations were normal. No further episodes of EO occurred, and follow-up showed normal testicular growth. This case adds weight to existing literature which suggests hematogenous spread as the most frequent cause of neonatal EO, without urinary tract abnormality. EO as cause of recurrent sepsis in the neonate after apparently adequate treatment of antecedent blood born infection is highlighted. Surgical exploration confirmed diagnosis, and evacuation of the pyocele assisted resolution of systemic sepsis and decompressed the testis.