Background: Vancomycin infusion reaction (VIR, previously known as “red man syndrome”) and anaphylaxis are two vancomycin hypersensitivity reactions with identical and clinically indistinguishable clinical presentations. Method: This was a retrospective study where vancomycin hypersensitivity cases who underwent vancomycin desensitization in the past two years were recruited. Results: Two vancomycin hypersensitivity cases were labeled as allergic to vancomycin in their previous hospitalizations before being admitted to our hospitals. The first case developed facial and lips swelling, while the second case developed transient hypotension; both occurred after the first dose of intravenous vancomycin, and hence were labelled as allergies without continuation of vancomycin in the previous hospitalizations. During current hospital admissions, both patients required vancomycin to treat infections. After weighing the risks and benefits, rapid vancomycin desensitization was conducted in both patients because of budget constraints in the public hospitals for alternative antibiotics. The desensitization was successfully conducted with no recurrence of previous reactions, and both cases completed intravenous vancomycin treatment for their infections. Conclusion: Clinical presentations in VIR and anaphylaxis might be identical and indistinguishable, especially the reactions that have happened in the past and confirmatory allergy test is not available. Our study reported that vancomycin desensitization could be conducted in cases where VIR or anaphylaxis are uncertain, with the past reactions not life-threatening, and if no other alternative antibiotic can be used to treat infections.