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Study question In couples with unexplained infertility, does IVF increase cumulative live birth rate and reduce multiple pregnancy rate compared to intrauterine insemination with ovarian stimulation (IUI-OS)? Summary answer There were no significant differences in cumulative live birth and multiple pregnancy rates between IVF and IUI-OS in couples with unexplained infertility. What is known already IVF and IUI-OS are widely used in managing unexplained infertility, especially in couples with a poor prognosis for natural conception. Although several randomized controlled trials (RCTs) have compared IVF versus IUI-OS, it remains inconclusive regarding which approach is more effective. Some of the RCTs did not define a time limit for follow up and others made the comparison on a per-cycle basis which provides a biased estimate in favour of IVF. Study design, size, duration We performed an individual participant data meta-analysis (IPD-MA) that synthesised available individual-level data comparing IVF and IUI-OS in unexplained infertility. We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register of RCTs and included eligible RCTs that completed data collection before June 2021. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. Participants/materials, setting, methods RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were included. The primary effectiveness outcome was cumulative live birth, defined by time to pregnancy leading to live birth. The primary safety outcome was the number of multiple pregnancies per participant. IPD were checked and standardised before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool. The analysis followed the intention-to-treat principle, and a two-stage IPD meta-analysis was performed. Main results and the role of chance Of eight potentially eligible RCTs, four shared individual-level data of 933 couples, of which 550 couples were allocated to IVF and 383 couples to IUI-OS. Two RCTs had a low risk of bias, one had some concerns, and one had a high risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 couples, 50.3% vs 43.2%, HR 1.10, 95% CI 0.54 to 2.21, I2  =  68.7%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than in IUI-OS (3 RCTs, 923 couples, 3.8% vs 5.2%, OR 0.78, 95% CI 0.41 to 1.50, I2  =  0.0%). Clinical pregnancy (4 RCTs, 933 couples, OR 1.09, 95% CI of 0.78 to 1.53, I2  =  14.3%) and pregnancy loss (3 RCTs, 760 couples, OR 0.97, 95% CI 0.55 to 1.72, I2  =  0.0%) were comparable between IVF and IUI-OS. There were no significant differences in neonatal outcomes between the two interventions on gestational age and birth weight. Limitations, reasons for caution Four RCTs did not share IPD which may introduce the risk of data availability bias. Only two included RCTs collected data on neonatal outcomes. Three of the included RCTs predominantly or only included couples with poor prognosis of natural conception which limits generalisability. Wider implications of the findings IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility, especially for those with a poor prognosis of natural conception. The associated costs of interventions and the preference of couples are important in clinical decision-making. Trial registration number not applicable