There are limited data on the efficacy of antibiotics in the management for meconium aspiration syndrome (MAS). This purpose of the prospective randomized controlled clinical trial compared the infection-related outcome of non-ventilated cases of MAS without perinatal risk factors for infection, treated with or without antibiotics therapy, as measured by the incidence of pneumonia and sepsis up to the age of 2 months. From January 1997 to July 2003, this study was carried out in our nursery. Infants with MAS without perinatal risk factors for infection and without ventilator use were randomly allocated to study and antibiotics groups after informed parental consent was obtained. The study group did not receive antibiotics, while the antibiotics group received antibiotics including ampicillin and gentamicin for 3 days until the blood cultures were negative, as was standard practice in the nursery. Other management and monitoring of MAS were the same in both groups. Of a total of 425 cases of MAS, 119 cases were excluded because there were at risk for infection or respiratory failure needing ventilator support. The study group comprised 148 cases and the antibiotics group 158 cases. Among these patients, 127 from the study group and 132 from the antibiotics group were followed up until 2 months of age. The profile of patients with respect to the method of delivery, the characteristics of meconium, Apgar score, sex, gestational age and birth body weight was similar in both groups. There were no significant differences in the duration of tachypnea, O2 supplementation and nasal continuous positive airway pressure (CPAP) between the two groups. Pneumothorax occurred in 4 cases in the study and 7 cases in the control group. There was no mortality in either group. Blood cultures at 6 and 72 h of age were all negative in both the study and the antibiotics groups. No infant developed bacterial pneumonia, sepsis or meningitis in the follow-up program at 2 months of age. We conclude that antibiotic treatment did not affect the clinical course and outcome related to infection in MAS without perinatal risk factors for infection and without ventilator use. The role of antibiotics in the management of MAS may need to be reevaluated in a study with a larger sample size.