Granuloma annulare is a fairly common entity yet lacks reliable treatment options especially when multiple lesions or dissemination exists. A recent case series suggests that a regimen of three oral antibiotics may prove to be an effective treatment. Our objective is to evaluate the efficacy of once monthly triple antibiotic therapy for granuloma annulare. We conducted an open-label prospective study of subjects with at least five lesions of granuloma annulare who received once monthly rifampin, ofloxacin, and minocycline for 6 months. Improvement was measured with a novel objective Granuloma Annulare Severity Index (GASI) scoring system. Twenty-one subjects enrolled. Ten subjects (48%) achieved at least a 50% reduction in their GASI, including three subjects (14%) who reached 75% improvement and one subject (5%) whose skin cleared. Six subjects (29%) had no change or worsening of their granuloma annulare. Median GASI scores decreased significantly by 15 points (p < 0.01), although the clinical significance of this result is unclear. As this was a small open-label study without a control group, we cannot determine if the results simply reflect the natural course of the disease. The GASI is not a validated assessment tool. Once monthly triple antibiotic use may improve but not clear granuloma annulare over 6 months. Randomized trials may be warranted to further assess this therapy.