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BACKGROUND Edinburgh Postnatal Depression Scale (EPDS) is a validated screening tool widely used to assess perinatal depression (PND). However, due to stigma associated with PND, respondents could answer sensitive questions differently depending on the mode of administration, especially in culturally and linguistically diverse country like India. The present study explored longitudinal differences in EPDS scores between self-administered and interviewer-administered modes OBJECTIVE The main objective of this study was to evaluate the differences in EPDS administration between the self-administered and interviewer-administered modes, a longitudinal observational study to understand and improve the test score interpretation. The present study explores differences in EPDS scores in assessing PND longitudinally, comparing self and interview-based modes of EPDS administration in perinatal women of rural South India METHODS 177 women from rural South India were administered EPDS, self-administration followed by interviewer-administered for four visits, twice each during prenatal and postnatal visits. EPDS scores were compared between the two modes descriptively, graphically and by repeated mixed measure models. Classification of antenatal depression (AD), postnatal depression (PD) and PND based on the two modes were compared by McNemar Chi-square test. Clinical and psychosocial characteristics were examined to identify factors associated with differences in the scoring modes. Concordance rates and Goodman Kruskal’s Gamma coefficients were measured for individual EPDS items. RESULTS Longitudinal EPDS scores and rates of AD, PD and PND were significantly higher in self-administered mode. Recent adverse life events were the only factor observed to be significantly associated with the differences between the two modes. Rank correlation and concordance rates suggested stronger association for EPDS items relating to anhedonia subscale and moderate/weaker association for EPDS items relating to anxiety/depression subscales. CONCLUSIONS Our study findings suggest that the effect of mode of administration should be taken into account while using PND screening tools such as EPDS, especially in countries such as India with higher levels of illiteracy. CLINICALTRIAL The study was registered with the Clinical Trials Registry of India, registration no. CTRI/2017/11/010497 and was conducted from October 2017 to May 2019.