The objective of this single-center, retrospective cohort study was to identify whether combination therapy is associated with a lower rate of adverse outcomes for the treatment of Gram negative non-HACEK IE. The primary endpoint was a composite of 60-day all-cause mortality, readmission, or recurrence of bacteremia. Of the 60 patients included, 56.7% met the primary composite outcome, with 20% overall mortality at 60 days. There was no difference in the primary composite outcome of 60-day readmission, infection recurrence or mortality between groups, with 62% of patients in the monotherapy group and 50% of patients in the combination therapy group experiencing the composite outcome (P = 0.36). Despite the high mortality and complicated nature of non-HACEK Gram negative IE, this study showed no difference in 60-day bacteremia recurrence, readmission or mortality among patients treated with combination therapy or monotherapy, suggesting that monotherapy may lead to similar clinical outcomes.