Treatment of latent tuberculosis infection (LTBI) is highly effective at preventing active tuberculosis (TB) disease. Understanding LTBI treatment practices in US health system settings is critical to identify opportunities to improve treatment prescription, initiation, and completion, and thus to prevent TB disease. We assessed LTBI treatment practices among a cohort of adults after their first positive LTBI test (tuberculin skin test [TST] or interferon gamma release assay [IGRA]) between 2009 and 2018 at 2 large integrated health systems in California. We described the prescription, initiation, and completion of LTBI treatment (isoniazid [INH], rifampin, and rifamycin-INH short-course combinations) by demographic and clinical characteristics. We used multivariable robust Poisson regression to examine factors that were independently associated with treatment prescription and completion. Among 79 302 individuals with a positive LTBI test, 33.0% were prescribed LTBI treatment, 28.3% initiated treatment, and 18.5% completed treatment. Most individuals were prescribed INH (82.0%), but treatment completion was higher among those prescribed rifamycin-INH short-course combinations (69.6% for INH + rifapentine and 70.3% for INH + rifampin) compared with those prescribed INH (56.3%) or rifampin (56.6%). In adjusted analyses, treatment prescription and completion were associated with older age, female sex, more comorbidities, immunosuppression, not being born in a high-TB incidence country, and testing positive with IGRA vs TST. LTBI treatment is underutilized, requiring tailored interventions to support treatment prescription and completion for patients with LTBI.