Background: Given the low first-pass success rate of the conventional short-axis (SAX) or long-axis (LAX) approach, ultrasound-guided radial artery cannulation in adults with radial artery diameters less than 2.2 mm may still be challenging. In this study, we compare the efficacy of modified long-axis in-plane(M-LAIP) versus short-axis out-of-plane (SAOP) or conventional palpation(C-P) approaches for ultrasound-guided radial artery cannulation.Methods: This was a prospective, randomized and controlled trial, conducted from 1 July 2018 to 24 November 2018. A total of 201 patients (age 18 to 85 years, the diameter of the radial artery less 2.2 mm) were included. All patients were randomized 1:1:1 to the M-LAIP, SAOP or conventional palpation (C-P) approach. The primary outcome was the cannulation success rate. Secondary outcomes included first location time and cannulation time, number of attempts. The Chi-square (χ2) test was used to compare categorical data between 3 groups.Results: The cannulation success rate was significantly higher in the M-LAIP group than in the SAOP or C-P groups (first success rate: 80.3% vs 53.8% or 33.8%; p < 0.001; total success rate: 93.9% vs 78.5% or 50.8%; p < 0.001). First location time (seconds) was significantly longer in the M-LAIP group (31(28-35[12-44])) than in the SAOP (15(14-17[10-21]); p < 0.001) and C-P groups (12(8-13.5 [6-37]). However, the cannulation time (seconds) in the M-LAIP group (29(24-45[16-313])) was significantly shorter than that in the SAOP (45(28.5-135.5[14-346]); p = 0.002) and the C-P groups (138(27-308[12-363]); p < 0.001). The number of attempts was lower in the M-LAIP group compared with SAOP or C-P group (1.29±0.63 vs 1.8±0.89 or 2.22±0.93, p < 0.001).Conclusions: The use of the M-LAIP approaches significantly improved the success rate of radial artery cannulation in adults with radial artery diameters less than 2.2 mm, compared with that achieved with the use of traditional short-axis out-of-plane approach.Trial registration: ClinicalTrials.gov; No: ChiCTR-IOR-17011474; URL: http: // www. chictr.org. cn/index.aspx. Registered 24 June 2018.