Research suggests that therapeutic communication could enhance patient comfort during medical procedures. Few studies have been conducted in clinical settings, with adequate blinding. Our hypothesis was that a positive message could lead to analgesia and anxiolysis, and that this effect would be enhanced by an empathetic interaction with the nurse performing the procedure, compared with an audio-taped message. This study aimed to modulate the contents and delivery vector of a message regarding peripheral intravenous catheter (PIC) placement in the emergency department (ED). This study was a 2 + 2 randomized controlled trial registered on ClinicalTrials.gov (NCT03502655). A positive versus standard message was delivered through audio tape (double-blind) in the first phase ( N = 131) and through the nurse placing the catheter (single-blind) in the second phase ( N = 120). By design, low practitioner empathic behavior was observed in the first phase (median, 1 of 5 points). In the second phase, higher empathic behavior was observed in the positive than in the standard message (median, 2 versus 3, p < .001). Contrary to our hypothesis, the intervention did not affect pain or anxiety reports due to PIC placement in either phase (all p values > .2). The positive communication intervention did not impact pain or anxiety reports after PIC. There might have been a floor effect, with low PIC pain ratings in a context of moderate pain due to the presenting condition. Hence, such a therapeutic communication intervention might not be sufficient to modulate a mild procedural pain in the ED.