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Background: During the last two decades, much effort is put to better understand the etiology of schizophrenia. Studying negative symptoms such as endophenotypes is a plausible approach to elucidate the genetic basis of schizophrenia. Neuregulin-1 (NRG1) is a key candidate gene to develop schizophrenia and its negative symptoms. The NRG1 variant rs6988339 was previously characterized as a schizophrenia susceptibility locus in different Scottish populations. Objectives: The current study aimed to examine the association of rs6988339 with schizophrenia and its negative symptoms in an Iranian population. Methods: The current case-controlled study enrolled 469 subjects (276 unrelated schizophrenia patients and 193 healthy controls). The study investigated the association of rs6988339 with schizophrenia and its negative symptoms (assessed with the positive and negative syndrome scale; PANSS) in an Iranian population. Results: The obtained results showed that rs6988339 was a schizophrenia susceptibility locus in the Iranian population, the minor allele G was the risk allele and A the protective allele (P = 0.0007). Of the four subscales of the PANSS test, the negative score showed the strongest association with this variant (P = 0.001). Conclusions: The results further supported the implication of NRG1 in the pathogenesis of negative symptoms in schizophrenia.