INTRODUCTION: Despite its numerous benefits, exclusive breastfeeding (EBF) remains an underutilized practice. Enhancing EBF uptake necessitates a focused approach targeting regions where its adoption is suboptimal. This study aimed to investigate regional disparities in EBF practices and identify determinants of EBF among infants aged 0-1, 2-3, and 4-5 months in Tanzania. METHODS: This cross-sectional study utilized data from the 2015/16 Tanzania Demographic and Health Survey. A total of 1,015 infants aged 0-5 met the inclusion criteria, comprising 378 aged 0-1 month, 334 at 2-3 months, and 303 at 4-5 months. EBF practices were assessed using a 24-hour recall method. A generalized linear mixed model, with fixed covariates encompassing infant and maternal attributes and clusters for enumeration areas (EAs) and regions, was employed to estimate EBF proportions. RESULTS: Regional disparities in EBF were evident among infants aged 0-1, 2-3, and 4-5 months, with decline in EBF proportions as an infant's age increases. This pattern was observed nationwide. Regional and EA factors influenced the EBF practices at 0-1 and 2-3 months, accounting for 17-40% of the variability at the regional level and 40-63% at the EA level. Literacy level among mothers had a significant impact on EBF practices at 2-3 months (e.g., women who could read whole sentences; AOR = 3.2, 95% CI 1.1,8.8). CONCLUSION: Regional disparities in EBF proportions exist in Tanzania, and further studies are needed to understand their underlying causes. Targeted interventions should prioritize regions with lower EBF proportions. This study highlights the clustering of EBF practices at 0-1 and 2-3 months on both regional and EA levels. Conducting studies in smaller geographical areas may enhance our understanding of the enablers and barriers to EBF and guide interventions to promote recommended EBF practices.