A Phase I, single-center investigation demonstrated that 8 weeks of antimycobacterial therapy improved sarcoidosis forced vital capacity (FVC). Safety and efficacy assessments have not been performed in a multicenter cohort.The objective of this study was to determine the safety and efficacy of anti-mycobacterial therapy on sarcoidosis physiologic and immunologic endpoints.and Methods: In a double-blind, placebo-controlled, multicenter investigation, pulmonary sarcoidosis patients were randomly assigned to receive 16-weeks of concomitant Levofloxacin, Ethambutol, Azithromycin and Rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percent of predicted FVC among patients randomized to CLEAR or placebo, in addition to their baseline immunosuppressive regimen. Secondary outcomes included Six-minute Walk Distance (6MWD), Saint George's Respiratory Questionnaire (SGRQ), adverse events, and decrease in mycobacterial ESAT-6 immune responses.The intention-to-treat (ITT) analysis revealed no significant differences in change of FVC among the 49 patients randomized to CLEAR (1.1% decrease), compared to the 48 randomized to placebo (0.02% increase) (p=0.64). Physiologic parameters, such as the change in 6MWD, were likewise similar (p=0.91); change in SGRQ favored the placebo (-8.0 for placebo vs -1.5 for CLEAR, p=0.028). The per-protocol (PP) analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 meters vs 6.3 meters, p=0.24) or SGRQ (-2.3 vs -7.0, p=0.14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR subjects (p=0.0003), but not placebo (p=0.24).Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiologic benefit in FVC or 6MWD among sarcoidosis patients.