Objective To investigate the impact of goal-oriented hemoperfusion (HP) with monitoring of the paraquat concentration on the prognosis of patients with acute paraquat poisoning. Methods This prospective observational study involved patients with acute paraquat poisoning admitted from March 2012 to September 2015. The patients received either goal-oriented or routine HP. All other treatments were the same between the two groups. The primary endpoint was 28-day mortality after poisoning. The secondary endpoints were the incidence of organ dysfunction within 7 days and 7-day mortality. Results Eighty-four patients were enrolled (49 in the control group and 35 in the goal-oriented group). The two groups were similar in terms of clinical characteristics. There was no significant difference in the incidence of organ dysfunction between the two groups within 1 week of admission. Mortality on day 7 was significantly lower in the goal-oriented than control group, but there was no difference on day 28. However, 28-day mortality was significantly lower in the goal-oriented group among patients with an oral dose of 50 ml. Conclusions HP with monitoring of the urine paraquat concentration as goal-oriented therapy can reduce the early mortality of paraquat poisoning.