Does the prevalence of 12-month infertility in Burkina Faso, Côte d'Ivoire, Kenya, and Uganda differ between women trying to conceive and the broader population of women exposed to unprotected sex, and how are prevalence estimates affected by model assumptions and adjustments? Estimates of 12-month infertility among tryers ranged from 8% in Burkina Faso to 30% in Côte d'Ivoire, increasing substantially among a larger population of women exposed to unprotected intercourse. While having a child is a fundamental human experience, the extent to which women and couples experience infertility is a neglected area of research, particularly in sub-Saharan Africa. Existing estimates of infertility in this region vary widely from 2% to 32%, however, potential impacts of variability in study populations and model assumptions have not been well-examined. We used cross-sectional nationally representative survey data from Burkina Faso, Côte d'Ivoire, Kenya, and Uganda. We employed a multi-stage cluster random sampling design with probability proportional to the size selection of clusters within each country to produce representative samples of women aged 15-49. Samples ranged from 3864 in Côte d'Ivoire to 9489 in Kenya. We created two analytic samples in each country-tryers and a broader sample of women exposed to unprotected sex-exploring differences in population characteristics and estimating the period prevalence of 12-month infertility using the current duration (CD) approach. We also examined the impact of several model assumptions within each of the two analytic samples, including adjustments for recent injectable contraceptive use, unrecognized pregnancy, infertility treatment, underreported contraceptive use, and sexual activity. Employing the CD approach among tryers produced an overall 12-month infertility prevalence of 7.9% (95% CI 6.6-12.7) in Burkina Faso, 29.6% (95% CI 15.3-100.0) in Côte d'Ivoire, 24.5% (95% CI 16.5-34.6) in Kenya, and 14.7% (95% CI 8.1-22.4) in Uganda. Results among women exposed to unprotected intercourse indicated much higher levels of infertility, ranging from 22.4% (95% CI 18.6-30.8) in Uganda to 63.7% (95% CI 48.8-87.9) in Côte d'Ivoire. Sensitivity analyses suggest infertility estimates are particularly sensitive to adjustments around pregnancy recognition timing and sexual activity, with little impact of adjustments for recent injectable contraceptive use, infertility treatment, and underreporting of traditional and coital dependent contraceptive use. There was substantial digit preference in responses at 12 months, particularly among the tryers, which could introduce bias. Data quality concerns in the reproductive calendar may impact the accuracy of the CD approach among the broader sample of women exposed to unprotected sex, particularly with regard to underreported contraceptive use, induced and spontaneous abortions, and unrecognized pregnancies. Lastly, we lacked information on postpartum amenorrhea or abstinence. Understanding the inconsistencies in definition and analytic approach and their implications for infertility estimation is important for reliably monitoring population-level infertility trends, identifying factors influencing infertility, improving prevention programs, and ensuring access to quality treatment and services. This study was supported by grants from the Bill & Melinda Gates Foundation (INV009639) and the National Institute of Child Health and Human Development (K01HD107172). The funders were not involved in the study design, analyses, manuscript writing, or the decision to publish. The authors have no conflicts of interest to declare. N/A.