Selective gastrointestinal decontamination (SDD) regimens, which vary and consist of topical antibiotic prophylaxis (TAP) and protocolized parenteral antibiotic prophylaxis (PPAP), are highly effective in preventing ICU-acquired infections. Appears to be valid only within randomized controlled studies (RCCTs). Confusingly, SDD is also a concept that, if true, implies benefits to the population. The concept of SDD can finally be validated in humans using the broad accumulated evidence base, including studies on TAP and PPAP using non-coherent control (NCC) as a natural experiment. However, this test does imply harm to the general population, with a higher event rate associated with his SDD use in the ICU context. Selective gastrointestinal decontamination (SDD) is a polymorphic antibiotic regimen and an untested concept. The SDD regimen appears to be highly effective in preventing ICU-acquired infections. The SDD concept began 50 years ago as part of an experiment to improve supportive care for patients with neutropenia. Similar to immunization measures, SDD concepts have implications for infection prevention for both individual patients and population groups. SDD has some confusing aspects. The application and composition of the SDD scheme is far from what was originally conceived. It is neither a single regime nor a protocol. Despite extensive studies in various patient groups of intensive care units, hematologists, and other immunocompromised patients, the mechanism of action, benefits, and associated risks remain unclear. The concept of SDD emerged 50 years before him, when neutropenia was a major limiting factor in the development of effective anti-leukemia chemotherapy. Pseudomonas and other Gram-negative (GN) bacteremia complicating chemotherapy-associated neutropenia are associated with high mortality. Protective isolation was necessary to prevent acquired infections in high-risk neutropenic patients during this period when there were few effective antipseudomonas antibiotics. The concept of SDD arose from studies using irradiated chimeric mice engrafted with leukemia cells, which are at high risk for fatal bloodstream infections from the gastrointestinal tract. Previous experiments showed that increased susceptibility to oral challenge by Salmonella enteritidis was associated with loss of normally present intestinal flora after previous antibiotic exposure. A novel observation in depleted mice was that this sensitivity varied with the timing and level of experimental antibiotic and radiation exposure, and that 'selective' antibiotic exposure prevented lethal bacteremia after radiation. Without protective isolation under these laboratory mice were at high risk. An incident of cross-infection with resistant Gram-negative bacteremia from monkeys housed in the same laboratory dramatically demonstrated this susceptibility with large losses of laboratory mice. Five surprising observations from these landmark experiments support the concept of SDD. First, exposure to orally administered antibiotics that protect the anaerobic flora allowed mice to tolerate radiation doses 2 Gy higher than mice not exposed to antibiotics. Second, oral administration of individual antibiotics such as streptomycin, kanamycin, and neomycin improved survival and decreased the incidence of bacteremia compared with the combined use of all three antibiotics. A single exposure to antibiotics probably caused a 'selective effect' on the intestinal flora. Implementation of the concept in clinical applications followed, as it was possible. As colonization resistance appeared to be most closely associated with anaerobic flora, this led to a "traffic light" classification of therapeutic antibiotics for at-risk patients. 'Red light' antibiotics such as amoxicillin and clindamycin with known activity against anaerobic flora should be avoided to minimize loss of formation resistance.