Background: Low levels of 25-hydroxyvitamin D [25(OH)D] are frequent in chronic kidney disease and are associated with adverse outcomes. The aim of this 5-year prospective study was to evaluate the effects of cholecalciferol supplementation on mineral metabolism, inflammation and cardiac parameters in hemodialysis (HD) patients. Methods: The study included 97 patients. Cholecalciferol was given after HD according to 25(OH)D baseline levels measured twice (end of winter and of summer). The 25(OH)D levels, circulating bone metabolism, inflammation parameters, brain natriuretic peptide (BNP), pulse pressure (PP), and left ventricular mass index (LVMI) were evaluated before and after supplementation. Results: There was a significant increase in 25(OH)D levels after supplementation (p < 0.001); however, serum calcium (p = 0.02), phosphorus (p = 0.018), and iPTH (p = 0.03) were decreased. Magnesium levels increased during the study (p = 0.03). A reduction in the number of patients under active vitamin D (p < 0.001) and in the dose and number of patients treated with darbepoetin (p = 0.02) was observed. Serum albumin increased (p < 0.001), and C-reactive protein decreased (p = 0.01). BNP (p < 0.001), PP (p = 0.007), and LVMI (p = 0.02) were significantly reduced after supplementation. Conclusions: Long-term cholecalciferol supplementation allowed correction of 25(OH)D deficiency, improved mineral metabolism with less use of active vitamin D, attenuated inflammation, reduced the dose of the erythropoiesis-stimulating agent, and improved cardiac dysfunction.