Cardiac injury triggers cellular responses involving both cardiomyocytes and nonmuscle cells to process cardiac structural remodeling. End-stage renal disease (ESRD), despite conventional dialysis, is associated with adverse cardiac remodeling and increased cardiovascular events. Intensification of hemodialysis with nocturnal home hemodialysis (NHD; five sessions per week; 6–8 hours per treatment) was associated with regression of left ventricular hypertrophy and downregulation of genes in apoptosis and fibrosis. In this pilot study, we hypothesize that NHD achieves its cardiac effects in part through attenuation of innate immune activation resulting in amelioration of cardiomyocytes apoptosis and fibrosis. Eight patients (4M:4F; age, 59 ± 9 years) with ESRD were studied. Half of the cohort was converted to NHD, whereas the rest of the patients were maintained on conventional hemodialysis (CHD). At baseline, CHD was associated with an increase in cardiomyocyte apoptosis detected by flow cytometry using Annexin V (mean fluorescence index in CHD and in normal control is 1.00 ± 0.05 vs. 0.66 ± 0.01, p < 0.05). After conversion to NHD, cardiomyocyte apoptosis was reduced compared with baseline CHD situation (p < 0.05) and approached that of normal control (0.59 ± 0.09 vs. 0.66 ± 0.01, p > 0.05). The CHD serum was associated with a coordinated augmentation innate immunity pathway, significantly increasing myeloid differentiation factor-88 and interleukin-1 receptor–associated kinase-4; NHD was able to reduce their levels. Heat shock protein 60 was augmented during CHD condition and fell after NHD. In addition, CHD increased fibroblast proliferation and myofibroblast transformation. Uremia is associated with activation of common innate immune signaling pathways leading to fibrosis and apoptosis. Amelioration of uremic clearance by NHD may attenuate this pathological signaling cascade.