STUDY QUESTION: Are there any differences in physical and psychosocial well-being among women undergoing modified natural cycle frozen embryo transfer (mNC-FET) with or without vaginal progesterone as luteal phase support (LPS)? SUMMARY ANSWER: Women undergoing mNC-FET with vaginal progesterone supplementation were more likely to experience physical discomfort but there was no difference in psychosocial well-being between the two groups. WHAT IS KNOWN ALREADY: mNC-FET can be carried out with or without vaginal progesterone as LPS, which has several side-effects. It is commonly known that fertility treatment can cause stress and psychosocial strain, however, most studies on this subject are conducted in fresh cycle regimes, which differ from NC-FET and results may not be comparable. STUDY DESIGN, SIZE, DURATION: This is a sub-study of an ongoing RCT investigating whether progesterone supplementation has a positive effect on live birth rate in mNC-FET. The RCT is conducted at eight fertility clinics in Denmark from 2019 and is planned to end primo 2024. The sub-study is based on two questionnaires on physical and psychosocial well-being added to the RCT in August 2019. On the time of data extraction 286 women had answered both questionnaires. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had answered both questionnaires were included in the sub-study. Participants were equally distributed, with 143 in each of the two groups. Participants in both groups received the same questionnaires at two time-points: on cycle day 2-5 (baseline) and after blastocyst transfer. Participants in the progesterone group had administered progesterone for 7 days upon answering the second questionnaire. All items in the questionnaires were validated. Items on psychosocial well-being originate from the Copenhagen Multi-Centre Psychosocial Infertility - Fertility Problem Stress Scale (COMPI-FPSS) and from the Mental Health Inventory-5. MAIN RESULTS AND THE ROLE OF CHANCE: Women receiving progesterone experienced more vaginal itching and/or burning than women in the non-progesterone group (P < 0.001). Women in the progesterone group also experienced more self-reported vaginal yeast infection, this was, however, not significant after adjustment for multiple testing (P/adjusted P = 0.049/0.881). No differences regarding psychosocial well-being were found between the two groups. Within the progesterone group, a shift toward feeling less 'downhearted and blue' was found when comparing response distribution at baseline and after blastocyst transfer (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: All items on physical symptoms were self-reported. The item on vaginal yeast infection was therefore not diagnosed by a doctor. Inclusion in the study required a few extra visits to the clinic, participants who felt more burdened by fertility treatment might have been more likely to decline participation. Women who experienced a lot of side-effects to progesterone prior to this FET cycle, might be less likely to participate. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in line with previous known side-effects to progesterone. Physical side-effects of progesterone should be considered before administration.