Left ventricular hypertrophy (LVH) and inflammation independently increase risk for death in people who receive hemodialysis. A nonrandomized, controlled trial was conducted of the effect of short daily (6 sessions/wk of 3 h each) or conventional (three sessions/wk of 4 h each) hemodialysis on LVH and inflammatory factors. A total of 26 short daily hemodialysis and 51 matched conventional hemodialysis patients were enrolled, and baseline and 12-mo measures of echocardiographic left ventricular mass index (LVMI), serum C-reactive protein (CRP), serum calcium and phosphorus, and erythropoietin resistance index were collected. Baseline characteristics were similar between groups except that hemoglobin and serum calcium were lower and serum phosphorus was higher in the short daily hemodialysis group. At 12-mo follow-up, short daily hemodialysis patients experienced a 30% decrease in LVMI (154 +/- 33 to 108 +/- 25; P < 0.0001). After adjustment for potential confounders, short daily hemodialysis (beta = -41.63, P = 0.03) and percentage decrease in serum phosphorus (beta = -0.12, P = 0.04) predicted a 12-mo decrease in LVMI. Among short daily hemodialysis patients, there were significant reductions in median CRP levels [1.22 interquartile range (IQR) (0.37 to 3.70) to 0.05 IQR (0.05 to 1.17); P < 0.01] and erythropoietin resistance index [19.5 IQR (8.6 to 37.6) to 10.5 IQR (5.5 to 14.6); P < 0.001]. There were no significant changes in LVMI, CRP, or erythropoietin resistance index in the conventional hemodialysis group. Short daily hemodialysis is associated with improved fluid and phosphorus management and a reduction in LVH and inflammatory factors compared with conventional hemodialysis. Future trials are needed to determine whether short daily hemodialysis can reduce morbidity and mortality in this high-risk population.