Frequent hemodialysis requires using the vascular access more often than with conventional hemodialysis, but whether this increases the risk for access-related complications is unknown. In two separate trials, we randomly assigned 245 patients to receive in-center daily hemodialysis (6 days per week) or conventional hemodialysis (3 days per week) and 87 patients to receive home nocturnal hemodialysis (6 nights per week) or conventional hemodialysis, for 12 months. The primary vascular access outcome was time to first access event (repair, loss, or access-related hospitalization). Secondary outcomes were time to all repairs and time to all losses. In the Daily Trial, 77 (31%) of 245 patients had a primary outcome event: 33 repairs and 15 losses in the daily group and 17 repairs, 11 losses, and 1 hospitalization in the conventional group. Overall, the risk for a first access event was 76% higher with daily hemodialysis than with conventional hemodialysis (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.11-2.79; P=0.017); among the 198 patients with an arteriovenous (AV) access at randomization, the risk was 90% higher with daily hemodialysis (HR, 1.90; 95% CI, 1.11-3.25; P=0.02). Daily hemodialysis patients had significantly more total AV access repairs than conventional hemodialysis patients (P=0.011), with 55% of all repairs involving thrombectomy or surgical revision. Losses of AV access did not differ between groups (P=0.58). We observed similar trends in the Nocturnal Trial, although the results were not statistically significant. In conclusion, frequent hemodialysis increases the risk of vascular access complications. The nature of the AV access repairs suggests that this risk likely results from increased hemodialysis frequency rather than heightened surveillance.