VLBW-infants below 1500 g of birth weight have a quite high risk to acquire a nosocomial sepsis. 20-40% of all infants exhibit signs of nosocomial infection once during neonatal intensive care. The rate of infection is related to technique and amount of used invasive devices as to gestational age. Coagulase-negative staphylococci (CONS) and gram-negative organisms contribute most to these cases of sepsis. In a three phase study we tried to demonstrate the efficacy of different mechanisms to change the rate of nosocomial sepsis. During the first phase a strict hygienical protocol was enforced as isolation, care with sterile gloves and aseptic techniques in introducing and maintaining i.v. lines. In a second phase we started a randomized controlled study of prophylactic vancomycin (10 mg/kg/day in two doses). In a third phase we added an oral antibiotic regime with cefixime for all patients with positive cultures for gramnegative organisms under the hypothesis of translocation from the gut as the way of infection. During the first phase 23.7% of 76 patients enrolled acquired CONS-sepsis, 0.52% gramnegative sepsis. During the second phase (41 patients) 6 patients in the control group acquired CONS-sepsis, none in the vancomycin-group. The rate of gramnegative infections was not different (4 and 3 cases). During the third phase (vancomycin plus cefixime eventually in cases of positive stool cultures) no case of nosocomial sepsis occurred (35 patients, 11 positive cultures). The management used in phase 3 reduced the rate of nosocomial infections in VLBW-infants drastically.