Background: Appropriate and accurate easy access tools are necessary to overcome complications from malpositioned line tips of peripherally inserted central catheters (PICCs) in critically ill neonates. Ultrasound is a radiationless, cost-beneficial, and time-saving method that allows medical personnel to manipulate the line and correct possible malposition of this tip. In addition, it reduces the need for a second radiography. Objectives: We compared the effectiveness of sonography with radiography for confirmation of the line tip placement. Methods: This prospective descriptive-analytical study was conducted in the Neonatal Intensive Care Unit (NICU) in Tehran Children’s Medical Center (tertiary level), Tehran, Iran. Neonates who were candidates for PICC implantation according to the ward’s protocol were enrolled in the study. Radiography and sonography were performed after catheter insertion by a radiologist blinded to the preliminary radiographic reports. The results of both methods were compared and interpreted by statistical analysis using the chi-square and Pearson correlation tests. Results: A total of 90 infants, 45 (50%) males and 45 (50%) females, were assessed. We noted that 17 (18.8%) cases had malpositioned tips according to the radiographs. Malpositioning of the line tips were identified in 21.1% of cases by sonography (P ≤ 0.05), which indicated a higher accuracy for sonography compared to radiography. Both methods were appropriately correlated regardless of the underlying variables. Sonography had a sensitivity of 100% and specificity of 89.5%, a positive predictive value (PPV) of 97.3%, and a negative predictive value (NPV) of 100%. Conclusions: Our findings show that sonography can be a more accurate, safer bedside tool, with fewer complications compared to radiography in PICC tip placement determination in neonates. Multi-center studies with increased sample sizes should be performed to confirm replacement of radiography by sonography as the gold standard test for confirmation of PICC tip positioning.