OBJECTIVE. Coupled ECG-electromagnetic (EM) guidance shows promise for use in placement of peripherally inserted central catheters (PICCs) when compared with the classic blind technique. However, ECG-EM guidance has not been appropriately compared with the reference standard of fluoroscopy (FX) guidance. Here, we aimed to compare ECG-EM guidance with FX guidance with regard to the final tip position of PICCs. SUBJECTS AND METHODS. A total of 120 patients (age range, 19-94 years) referred for PICC placement were randomized to the ECG-EM or FX group. All interventions were performed by PICC team members who had the same standardized training and experience. Final tip position was assessed using chest radiography and was classified as optimal, suboptimal, or inadequate requiring repositioning on the basis of the distance from the PICC tip to the cavoatrial junction (CAJ). Statistical analyses were performed using the Mann-Whitney U test for final catheter tip position (mean distance from CAJ) and Fisher and chi-square tests for proportions. RESULTS. PICCs were successfully inserted in 118 patients (53 men and 65 women). Catheter tip positions were optimal or suboptimal in 100% of the FX group and 77.2% of the ECG-EM group. Furthermore, precision of placement was significantly better (p = .004) in the FX group (mean distance from the PICC tip to the CAJ = 0.83 cm) than in the ECGEM group (mean distance from the PICC tip to the CAJ = 1.37 cm). Thirteen (22.8%) of the PICCs placed using ECG-EM guidance, all of which were inserted from the left side, were qualified as inadequate requiring repositioning and required another intervention. CONCLUSION. Our results revealed significant differences in final tip position between the ECG-EM and FX guidance techniques and indicate that ECG-EM guidance cannot appropriately replace FX guidance among unselected patients. However, ECGEM guidance could be considered as an acceptable technique for patients in whom the PICC could be inserted from the right side. TRIAL REGISTRATION. ClinicalTrials.gov NCT03652727.