AbstractBackgroundPeople experiencing homelessness (PEH) are disproportionately diagnosed with active tuberculosis. While promoting latent tuberculosis infection (LTBI) treatment has been a call to action, PEH engaging in substance use often experience challenges in completing LTBI treatment.MethodsIn this non‐randomized single arm study, we tested an innovative, community‐based, nurse‐led community health worker (RN‐CHW) model, on reducing drug use among 50 PEH, residing in homeless shelters or living on the streets in Los Angeles. Follow‐up was at 3‐ and 6‐ months.ResultsFindings revealed significant and ongoing decrease in any drug use (odds ratio [OR] = 0.30; 95% confidence interval [CI] = 0.14—0.68); p = .004), amphetamine use (OR = 0.14; 95% CI = 0.02–0.81; p = .029), cannabis use (OR = 0.26; 95% CI = 0.12–0.57; p = .001) and methamphetamine use (OR = 0.30; 95% CI = 0.10–0.90; p = .031) at 6‐month follow‐up.ConclusionsTo our knowledge, this pilot study is the first to evaluate the impact a RN‐CHW delivered intervention on reduction in drug use among PEH enrolled in a LTBI intervention. LTBI interventions may serve as an entryway into reduction in drug use among this underserved population.