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Objectives: Approximately 40% of tuberculosis (TB) cases remain undiagnosed globally. Lower lung field TB (LLF TB) presents atypically and is often misidentified as other lung diseases, leading to diagnostic delays in resource-limited settings. It may contribute to increased TB transmission and mortality. We aimed to identify microbiological determinants of LLF TB and evaluate treatment responses to optimize care. Methods: We conducted an observational cohort study in Lima, Peru, enrolling adults with microbiologically confirmed pulmonary TB (PTB) diagnosed by GeneXpert MTB/RIF assay or sputum culture. Mycobacterium tuberculosis (MTB) lineage was determined using whole-genome sequencing. Due to the delayed chest radiograph changes in LLF TB compared to non-LLF TB, we measured changes in the St. George's Respiratory Questionnaire (SGRQ) score at 2-month treatment mark and evaluated World Health Organization-specified final treatment outcomes. We used logistic regression to evaluate the associations between LLF TB and microbiological determinants and treatment outcomes. We used linear regression to assess whether the change in SGRQ scores over the first 2 months of treatment varied by LLF TB status. Results: Among 1316 PTB patients, 84 (6%) had LLF TB. Compared to non-LLF TB patients, LLF TB patients were more likely to be smear-negative (adjusted odds ratio [aOR] [95% CI] = 2.04 [1.28-3.23], P = 0.002) and to be infected with Lineage 2 (aOR [95% CI] = 1.95 [95% CI: 1.07-3.41; P = 0.024]). People with LLF TB had less improvement in SGRQ scores after 2 months of treatment (adjusted score difference [95% CI] = –6.29 [–10.99 to –1.59], P = 0.009), while they experienced better final outcomes compared to non-LLF TB patients, though this difference did not reach statistical significance (aOR = 0.43 [95% CI: 0.13-1.05], P = 0.103). Conclusion: Patients with LLF TB are more likely than those with upper lung lesions to be sputum-negative on conventional tests, to be infected with Lineage 2, and to show less clinical improvement after treatment.