Understanding the pathogenesis of non-iatrogenic comorbidities of schizophrenia may provide insights into the pathogenesis of schizophrenia itself. First-episode, drug-naïve schizophrenia patients are at high risk of thromboembolic events, diseases related to substance abuse, sexual dysfunction, reproductive disorders, inflammatory and autoimmune diseases, as well as complications of hyperinsulinemia or hyperhomocysteinemia. This review focuses on the role of reduced plasminogen activator activity in non-iatrogenic comorbidity of schizophrenia. By preventing thrombus dissolution, low tissue plasminogen activator activity increases the risk of thrombotic events. Components of the plasminogen activator system also play a key role in reproduction. Both illicit drugs and tobacco increase plasminogen activator levels in the central nervous system, which seems to relieve symptoms of the mental disorder. Chronic alcoholism, sexual dysfunction, inflammatory and autoimmune disorders, and complications of hyperinsulinemia or hyperhomocysteinemia are somehow related to low plasminogen activator activity. Plasminogen activator mediates several neurochemical processes that seem to prevent or reverse gray-matter atrophy seen in first-episode schizophrenia patients. Such processes include cleavage of brain-derived neurotrophic factor precursor to an anti-apoptotic neurotrophin and activation of N-methyl-D-aspartate receptor. Controlled, randomized studies are needed to determine if measures aimed at correcting plasminogen activator activity can improve the quality of life, reduce morbidity and mortality rates, and particularly improve the course of schizophrenia.