<jats:title>Abstract</jats:title><jats:p>The upper respiratory tract is an obliged pathway for respiratory pathogens and a healthy microbiota may support the host's mucosal immunity preventing infection. We analyzed the nasopharyngeal microbiome in tuberculosis household contacts (HHCs) and its association with latent tuberculosis infection (TBI). A prospective cohort of HHCs was established and latent TBI status was assessed by serial interferon-γ release assay (IGRA). Nasopharyngeal swabs collected at baseline were processed for 16S rRNA gene sequencing. The 82 participants included in the analysis were classified as: (a) non-TBI [IGRA negative at baseline and follow-up, no active TB (n = 31)], (b) pre-TBI [IGRA negative at baseline but converted to IGRA positive or developed active TB at follow-up (n = 16)], and (c) TBI [IGRA positive at enrollment (n = 35)]. Predominant phyla were <jats:italic>Actinobacteriota</jats:italic>, <jats:italic>Proteobacteria</jats:italic>, <jats:italic>Firmicutes</jats:italic> and <jats:italic>Bacteroidota</jats:italic>. TBI group had a lower alpha diversity compared to non-TBI (p<jats:sub>adj</jats:sub> = 0.04) and pre-TBI (p<jats:sub>adj</jats:sub> = 0.04). Only TBI and non-TBI had beta diversity differences (p<jats:sub>adj</jats:sub> = 0.035). Core microbiomes’ had unique genera, and genus showed differential abundance among groups. HHCs with established latent TBI showed reduced nasopharyngeal microbial diversity with distinctive taxonomical composition. Whether a pre-existing microbiome feature favors, are a consequence, or protects against <jats:italic>Mycobacterium tuberculosis</jats:italic> needs further investigation.</jats:p>
