Plasma exchange (PE) is often performed in combination with hemodialysis (HD) or hemodiafiltration. However, most methods were developed for the treatment of renal failure, so various problems may arise during treatment of liver failure (LF). In this study, we investigated the impact of PE alone and in combination with HD, and we assessed the complications of using PE + HD for the treatment of LF. After the exchange of 1 L of fresh frozen plasma (FFP), we measured serum electrolytes, HCO3−, citrate, and acetate at 3 points in the circuit: A) the plasma separator inflow; B) after mixing of FFP/the dialyzer inflow; and C) the dialyzer outflow. Serum levels of human hepatocyte growth factor (HGF), acetate, and citrate were also measured before and after PE + HD. The levels of K+, Ca++, HCO3−, and acetate were significantly decreased, and citrate was increased, between A and B. K+ and citrate were decreased, while Ca++, HCO3−, and acetate showed an increase between B and C. Comparison of A with C revealed insufficient correction of the Ca++ and citrate levels by HD. After PE + HD, serum levels of acetate and citrate were increased, while HGF was decreased. We concluded that i) when PE is performed, HD is also necessary for correction, but achieves insufficient correction of Ca++ and citrate, ii) PE is non-selective and not only removes toxins but also beneficial substances such as HGF, iii) accumulation of acetate occurred, even with bicarbonate dialysate, since it also contains acetate for acidification.