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Peripheral venous cannulation is one of the most common procedures in medicine. A larger cannula allows higher rates of fluid to be provided if needed in a deteriorating patient; however, it is also perceived that larger-gauge cannula placement is associated with increased pain and procedural difficulty. This study aimed to compare the pain and procedural difficulty experienced during insertion between 18-gauge (18G) and 20-gauge (20G) cannulas. We conducted a single-blinded, randomized controlled trial on adult patients who required peripheral IV cannulation within a tertiary hospital emergency department between April and October 2018. Patients were randomized to either the 18G or 20G cannula group. The primary outcomes of the study—pain experienced by patients and procedural difficulties experienced by clinical staff—were recorded on two separate 10-cm visual analog scales. Other outcomes include first-attempt success rate, operator designation, complications, and the intent and actual use of the IV cannula were documented on preformatted questionnaires. Data from 178 patients were included in the analysis. Eighty-nine patients were allocated to each cannula group. There were no statistically or clinically significant differences between mean pain score (0.23; 95% CI 0.56–1.02; p = 0.5662) and mean procedural difficulty score (0.12; 95% CI 0.66–0.93; p = 0.7396). between the two groups. There was no difference in first-attempt success rate (73 of 89 vs. 75 of 89; p = 0.1288), complications (2 of 89 vs. 1 of 89) between the 20G group and 18G group, respectively. There was no significant difference between the 18G or 20G cannula for either pain experienced by patients or procedural difficulty experienced by clinicians. [ABSTRACT FROM AUTHOR]