The present study aims at investigating the association between common and rare variants of mitochondrial DNA (mtDNA), and increased risk of schizophrenia (SZ) and bipolar disorder (BPD) in a cohort of patients originating from the same Italian population. The distribution of the major European mtDNA haplogroups was determined in 89 patients and their frequencies did not significantly differ from those observed in the Italian population. Moreover, 27 patients with high probability of having inherited the disease from the maternal side were selected for whole mitochondrial genome sequencing to investigate the possible presence of causative point mutations. Overall, 213 known variants and 2 novel changes were identified, but none of them was predicted to have functional effects. Hence, none of the sequence changes we found in our sample could explain the maternal component of SZ and BPD predisposition. Keywords: bipolar disorder; mtDNA variants; schizophrenia INTRODUCTION Schizophrenia (SZ) and bipolar disorder (BPD) are among the top ten causes of disability worldwide. 1 Despite extensive genetic and pharmacological studies, the etiology and pathophysiology of these mental disorders are still unknown, and the nuclear susceptibility loci identified so far can explain only a small fraction of the genetic component of these diseases. 2 The growing body of observations published in the last decade points to the involvement of mitochondria in the pathophysiology of psychiatric disorders, including SZ and BPD. 3 Several genetic studies reported association between these diseases and common mitochondrial DNA (mtDNA) polymorphisms defining ethnic-specific mitochondrial haplogroups. [4][5] Other analyses found new rare variants with a putative functional effect 6 and a global excess of synonymous substitutions in the dorsolateral prefrontal cortex of SZ patients. 7 Despite the great interest of these findings, the role of mtDNA in the pathogenesis of SZ/BDP remains unclear.The present study aims at investigating the association between common and rare variants of mtDNA and the increased risk of SZ/ BPD in a sample of patients originating from the same Italian population.