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BackgroundHuman tuberculosis (TB) is caused by seven phylogenetic lineages of the Mycobacterium tuberculosis complex (MTBC), Lineage 1-7. Recent advances in rapid genotyping of MTBC based on single nucleotide polymorphisms (SNP), allow for phylogenetically robust strain classification, paving the way for defining genotype-phenotype relationships in clinical settings. Such studies have revealed that, in addition to host and environmental factors, strain variation in the MTBC influences the outcome of TB infection and disease. In Tanzania, such molecular epidemiological studies of TB however are scarce in spite of a high TB burden.Methods and findingsHere we used SNP-typing to characterize a nationwide collection of 2,039 MTBC clinical isolates representative of 1.6% of all new and retreatment TB cases notified in Tanzania during 2012 and 2013. Four lineages, namely Lineage 1-4 were identified within the study population. The distribution and frequency of these lineages varied across regions but overall, Lineage 4 was the most frequent (n = 866, 42.5%), followed by Lineage 3 (n = 681, 33.4%) and 1 (n = 336, 16.5%), with Lineage 2 being the least frequent (n = 92, 4.5%). We found Lineage 2 to be independently associated with female sex (adjusted odds ratio [aOR] 2.14; 95% confidence interval [95% CI] 1.31 - 3.50, p = 0.002) and retreatment cases (aOR 1.67; 95% CI 0.95 - 2.84, p = 0. 065) in the study population. We found no associations between MTBC lineage and patient age or HIV status. Our sublineage typing based on spacer oligotyping on a subset of Lineage 1, 3 and 4 strains revealed the presence of mainly EAI, CAS and LAM families. Finally, we detected low levels of multidrug resistant isolates among a subset of 144 retreatment cases.ConclusionsThis study provides novel insights into the MTBC lineages and the possible influence of pathogen-related factors on the TB epidemic in Tanzania.