This study investigated whether N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels could serve as prognostic indicators of the therapeutic responsiveness of the patent ductus arteriosus to pharmacologic treatment. The levels of NT-proBNP in premature neonates with hemodynamically significant patency of the ductus arteriosus (hsPDA) were assessed before and after treatment using ibuprofen, indomethacin, or both. The baseline NT-proBNP levels were similar in both the infants who responded and those who did not respond to medical treatment. The combined data for all the subjects showed that NT-ProBNP decreased after treatment, but the decrease did not correlate significantly with treatment success or failure. Of the 38 infants, 11 did not respond to treatment with ductal closure. Although the pretreatment NT-proBNP levels were similar, the posttreatment levels in the nonresponders remained significantly higher than in the responders. Moreover, in 3 (27%) of the 11 nonresponders, NT-proBNP actually increased rather than decreased with treatment. The NT-proBNP levels of seven infants increased over the course of the study. Within this group, however, the pretreatment NT-proBNP levels were significantly lower than in the overall population, with no differences in the posttreatment levels. Overall, the decrease in NT-proBNP with treatment, presented as the ratio of pretreatment–post-treatment/pretreatment was not well correlated with the ductal therapeutic outcome. In summary, in the study population, NT-proBNP was not sufficiently sensitive for accurate prediction of ductal therapeutic responsiveness.