Organophosphate (OP) compounds are frequently used agorchemicals for deliberate self-harm in some parts of the world resulting in high mortality and morbidity. Pralidoxime (2PAM) is the most widely used and trialed oxime for treatment of OP poisoning. There have been variations over the results of trials using 2PAM for OP poisoning. 2PAM therapy has led to favorable outcomes in some studies, whereas it has been associated with unfavorable outcomes or without benefit in the others. Why 2PAM works in some trials and why it does not in the others, has been a key question for medical toxicologists with no definite answer. In this systematic review, we sought to investigate possibilities of the variations in the results of different studies conducted on the effectiveness of 2PAM therapy for OP poisoning and we tried to provide solutions for future studies.