Initiation of breast-feeding within 1 h after birth has been associated with reduced neonatal mortality in a rural Ghanaian population. In South Asia, however, breast-feeding patterns and low birth weight rates differ and this relationship has not been quantified. Data were collected during a community-based randomized trial of the impact of topical chlorhexidine antisepsis interventions on neonatal mortality and morbidity in southern Nepal. In-home visits were conducted on d 1-4, 6, 8, 10, 12, 14, 21, and 28 to collect longitudinal information on timing of initiation and pattern of breast-feeding. Multivariable regression modeling was used to estimate the association between death and breast-feeding initiation time. Analysis was based on 22,838 breast-fed newborns surviving to 48 h. Within 1 h of birth, 3.4% of infants were breast-fed and 56.6% were breast-fed within 24 h of birth. Partially breast-fed infants (72.6%) were at higher mortality risk [relative risk (RR) = 1.77; 95% CI = 1.32-2.39] than those exclusively breast-fed. There was a trend (P = 0.03) toward higher mortality with increasing delay in breast-feeding initiation. Mortality was higher among late (> or = 24 h) compared with early (< 24 h) initiators (RR = 1.41; 95% CI = 1.08-1.86) after adjustment for low birth weight, preterm birth, and other covariates. Improvements in breast-feeding practices in this setting may reduce neonatal mortality substantially. Approximately 7.7 and 19.1% of all neonatal deaths may be avoided with universal initiation of breast-feeding within the first day or hour of life, respectively. Community-based breast-feeding promotion programs should remain a priority, with renewed emphasis on early initiation in addition to exclusiveness and duration of breast-feeding.