Erythropoietin (EPO) effects on cognition were for ages attributed to increased hemoglobin. Even after discovery of EPO/EPO receptor (EPOR) in brain, preclinical studies employed EPO mainly as neuroprotectant. Clinical trials (schizophrenia, multiple sclerosis, preterm infants) found brain matter protection and superior cognition upon EPO, particularly of processing speed/working memory. EPO treatment of juvenile mice achieved better learning/memory/attention, paralleled by enhanced hippocampal long-term potentiation. For mechanistic insight, we created a mouse model, overexpressing continuously active EPOR under a-calcium/calmodulin-dependent protein kinase II (a-CaMKII) promoter, i.e. in pyramidal neurons (cortex/hippocampus). In this model, we found a boost of higher cognition. Together, these results imply a role for EPO in neuroplasticity/higher cognition. We hypothesized that a respective relevance of the EPO/EPOR system would also be reflected by genetic variation of encoding genes. For addressing this hypothesis, we took advantage of the GRAS (Göttingen Research Association for Schizophrenia) data collection, providing a unique ground for phenotype-based genetic association studies (PGAS). GRAS comprises >1,000 patients with schizophrenia (DSM-IV-TR). DNA samples of GRAS patients were genotyped for genetic polymorphisms of EPO/EPOR. For statistical analyses, age, sex, negative symptoms, and duration of disease were used as covariates. Genotype-phenotype analysis, targeting higher cognition revealed significant associations of EPO/EPOR variants - alone and combined - with processing speed/working memory but not with blood readouts. The data show that genetic variants of the EPO/EPOR system influence cognition of schizophrenic individuals. Their interaction will help providing mechanistic insight into the molecular interplay between EPO and EPOR regarding cognition.