Background: Peripheral intravenous catheter (PIVC) insertion is the most common invasive procedure in the hospital setting. Ultrasound guided PIVC insertion in specific populations and settings has shown patient care benefits. Objective: To compare the success rate of first attempts of ultrasound guided PIVC insertion performed by nurse specialists with conventional PIVC insertion performed by nurse assistants. Method: Randomized, controlled, single-center clinical trial registered on the ClinicalTrials.gov platform under registration NTC04853264, conducted at a public university hospital from June to September 2021. Adult patients hospitalized in clinical inpatient units with an indication for intravenous therapy compatible with a peripheral venous network were included. Participants in the intervention group (IG) received ultrasound guided PIVC performed by nurse specialists from the vascular access team, while those in the control group (CG) received conventional PIVC by nurse assistants. Results: The study included a total of 166 patients: IG ( n = 82) and CG ( n = 84), mean age 59.5 ± 16.5 years, mostly women ( n = 104, 62.7%) and white ( n = 136, 81.9%). Success rate on the first attempt of PIVC insertion in IG was 90.2% and in CG was 35.7% ( p < 0.001), with a relative risk of 2.5 (95% CI 1.88–3.40) for success in IG versus CG. Overall assertiveness rate was 100% in IG and 71.4% in CG. Regarding procedure performance time, the medians in IG and CG were 5 (4–7) and 10 (6–27.5) min respectively ( p < 0.001). As for the incidence of negative composite outcomes, IG had lower rates compared to CG, 39% versus 66.7% ( p < 0.001), generating a 42% lower probability of negative outcomes in IG, 0.58 (95% CI: 0.43–0.80). Conclusion(s): Successful first-try insertion was higher in the group receiving ultrasound-guided PIVC. Moreover, there were no insertion failures and IG presented lower insertion time rates and incidence of unfavorable outcomes.