Background and objectives Autologous arteriovenous fistula (AVF) is the best vascular access for hemodialysis. Distal forearm radiocephalic fistula is the best option, although the primary failure rate ranges from 20% to 50%. The main objective of the PHYSICALFAV trial was to evaluate the effect of preoperative isometric exercise on vascular caliber, percentage of distal arteriovenous fistula, and primary failure rate. Design, setting, participants, and measurements The PHYSICALFAV trial (NCT03213756) is an open-label, multicenter, prospective, randomized, controlled trial (RCT). A total of 138 patients were randomized 1:1 to the exercise group (exercises combining a handgrip device and an elastic band for 8 weeks) or the control group (no exercise) and followed up with periodic Doppler ultrasound (DU) examinations. Results After 8 weeks of preoperative isometric exercise, in the exercise group, significant increases were detected in venous caliber (2.80 ± 0.95 mm vs 3.52 ± 0.93 mm p < 0.001), arterial caliber (2.61 ± 0.82 mm vs 2.74 ± 0.80 mm p = 0.008), arterial peak systolic velocity (66.34 ± 19.2 cm/s vs 71.03 ± 21.5 cm/s p 0.043), and maximum strength (28.35 ± 9.16 kg vs 32.68 ± 10.8 kg p < 0.001). Distal radiocephalic fistulas were performed in 75% of the exercise group patients compared with 50.8% in the control group (p = 0.030). The global primary failure rate was very low in both groups (7% exercise group vs 14% control group p = 0.373). Conclusion Isometric preoperative exercise can improve vascular caliber and increase the possibility of performing distal arteriovenous fistula, with no significant differences in primary failure rate.