OBJECTIVES:: The Micropuncture® 21-gauge needle may reduce complications related to vessel trauma from inadvertent venous or posterior arterial wall puncture. METHODS:: This was a single-center, multiple-user trial. Four hundred and two patients undergoing possible or definite percutaneous coronary intervention (PCI) were randomized 1:1 to an 18-gauge versus a 21-gauge needle. Patients and personnel pulling the sheaths and performing the follow-up were blinded. The primary end point was a composite of access bleeding. Events were tabulated following sheath removal, ≤24 h after the procedure and at the follow-up (at 1-2 weeks). End points were blindly adjudicated. RESULTS:: The event rate overall was 12.4% and did not differ significantly between groups, although the 21-gauge needle was found to reduce events by more than one third. An exploratory subgroup analysis of prespecified variables indicated that: patients who did not undergo PCI or elective procedures, female patients and those with a final sheath size of ≤6 Fr all had a significant or near-significant reduction of complications with Micropuncture. CONCLUSIONS:: Although no significant differences between the use of the 18- and 21-gauge needles were observed, there was a 50-75% reduction with Micropuncture in several subgroups. The study was terminated prematurely. Access site complications may be reduced by the use of the 21-gauge needle, particularly when the risk of bleeding is not high. Further multicenter data will be required to confirm these hypothesis-generating observations.