Introduction: Postpartum depression (PPD) is a common disorder and a type of clinical depression that affects mothers during the first 4 weeks after childbirth. Considering the destructive effects of this disease on mothers' behavior, identifying the factors affecting PPDand using proper methods in normal delivery is important. The aim of this study was to determine the relationship between regional anesthesia (RA) during labor and the incidence of PPDin women referred to hospitals affiliated to Shahid Beheshti University of Medical Sciences. Methodology: In this study, 200 pregnant women referred to hospitals of Shahid Beheshti University of Medical Sciences during 2015 to 2017 entered into two equal groups, Group R, administered RA, and Group C; control group without RA according to their desire. Each group consisted of 100 parturients, and the two groups were compared for the incidence of PPD and the association of depression with RA during labor. Results: Based on the obtained data, the participants in the two groups did not differ significantly in terms of age, body mass index (BMI), duration of delivery phases and depression in the first week of postpartum. However, the severity of pain in different phases of delivery was different due to the use of anesthetic for one of the groups. No significant relationship between RA and depression was observed in the first week after childbirth. However, RA has a significant relationship with PPD in the 4th week, so that the use of RA reduces the incidence of PPD in the 4th week (p = 0.066). Conclusion: We conclude that the use of regional anesthesia will not have a significant effect on postpartum depression in the first week, but it reduces the incidence of postpartum depression in the 4th week after childbirth. Citation: Barooti E, Malek B, Honarmand S, Moshari M, Alshohadaei SMS. Investigating the association of regional anesthesia during labor with postpartum depression. Anaesth pain & intensive care 2019;23(3):----  Received – 30 May 2018, Reviewed – 23 August, 26 October 2018, 2 May, 4 May, 16 June, 14 September 2019; Revised – 14 October 2018, 18 March, 10 June 2019; Accepted- 14 September 2019