<jats:p>The ultrasound-guided long-axis in-plane approach for central venous catheterization in infants and small children can prevent posterior wall penetration. The combined short-axis out-of-plane and long-axis in-plane approach reportedly prevents such penetration in adults. To test the hypothesis of non-inferiority of the combined approach to the long-axis in-plane approach, we compared the two approaches in infants and small children. Patients were randomized based on whether they underwent ultrasound-guided internal jugular vein catheterization using the combined or long-axis in-plane approach. Posterior wall penetration rates, first-attempt success rates, overall success rates within 20 min; scanning, puncture, and procedure durations; and number of attempts were compared between the groups. In the combined and long-axis in-plane groups (<jats:italic>n</jats:italic> = 55 per group), the posterior wall penetration rates were 5.5% (3/55) and 3.6% (2/55) (<jats:italic>P</jats:italic> = 0.65), the first-attempt success rates were 94.5% (52/55) and 92.7% (51/55) (<jats:italic>P</jats:italic> = 0.70), and the overall success rates within 20 min were 100% (55/55) and 98.2% (54/55) (<jats:italic>P</jats:italic> = 0.32), respectively. In the combined and long-axis in-plane groups, the median (interquartile range) scanning durations were 21 (16.5–34.8) s and 47 (29.3–65) s (<jats:italic>P</jats:italic><0.0001), the puncture durations were 114 (83–170) s and 74 (52.3–117.3) s (<jats:italic>P</jats:italic> = 0.0002), and the procedure durations were 141 (99–97.8) s and 118 (88.5–195.5) s (<jats:italic>P</jats:italic> = 0.14), respectively. The median number of attempts was 1 (interquartile range: 1–1, range: 1–3) in both groups (<jats:italic>P</jats:italic> = 0.72). Similar to the long-axis in-plane approach, the combined approach for internal jugular vein catheterization prevented posterior wall penetration in infants and small children.</jats:p> <jats:p><jats:bold>Trial registration:</jats:bold> This trial was registered before patient enrollment in the University Hospital Medical Information Network Clinical Trials Registry, registration number <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000044907" xlink:type="simple">UMIN000039387</jats:ext-link> (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000044907" xlink:type="simple">https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000044907</jats:ext-link>).</jats:p>