Background Risk-targeted testing and treatment of latent tuberculosis infection (LTBI) is a critical component of the United States’ (US) tuberculosis (TB) elimination strategy, but relatively low treatment completion rates remain a challenge. Both treatment persistence and completion may be facilitated by diagnosing LTBI using interferon gamma release assays (IGRA) rather than tuberculin skin tests (TST). Methods We used a national sample of administrative claims data to explore associations diagnostic test choice (TST, IGRA, TST with subsequent IGRA) and treatment persistence and completion in persons initiating a daily dose isoniazid LTBI treatment regimen in the US private healthcare sector between July 2011 and March 2014. Associations were analyzed with a generalized ordered logit model (completion) and a negative binomial regression model (persistence). Results Of 662 persons initiating treatment, 327 (49.4%) completed at least the 6-month regimen and 173 (26.1%) completed the 9-month regimen; 129 (19.5%) persisted in treatment one month or less. Six-month completion was least likely in persons receiving a TST (42.2%) relative to persons receiving an IGRA (55.0%) or TST then IGRA (67.2%; p = 0.001). Those receiving an IGRA or a TST followed by an IGRA had higher odds of completion compared to those receiving a TST (aOR = 1.59 and 2.50; p = 0.017 and 0.001, respectively). Receiving an IGRA or a TST and subsequent IGRA was associated with increased treatment persistence relative to TST (aIRR = 1.14 and 1.25; p = 0.027 and 0.009, respectively). Conclusions IGRA use is significantly associated with both higher levels of LTBI treatment completion and treatment persistence. These differences are apparent both when IGRAs alone were administered and when IGRAs were administered subsequent to a TST. Our results suggest that IGRAs contribute to more effective LTBI treatment and consequently individual and population protections against TB.