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BACKGROUND: Antibiotics have been widely used for the management of acne vulgaris, which has led to increased resistance of Cutibacterium acnes (C. acnes). OBJECTIVES: We sought to determine the susceptibility profile of C. acnes, isolated from patients with acne, to different prescribed antibiotics and compare our findings with global data. The relationship between antibiotic resistance and sex, age, acne severity, presence of any affected siblings, disease duration, and previous antimicrobial treatment was also investigated. METHODS: Samples were collected from randomly selected pustular acne lesions of patients attending the Dermatology Outpatients Clinic at Sir Paul Boffa Hospital in Floriana, Malta. Samples were inoculated and incubated in anaerobic conditions until 100 cultured C. acnes samples were obtained. Antibiotic susceptibility testing was then performed using azithromycin, clindamycin, doxycycline, minocycline, tetracycline, and trimethoprim/sulfamethoxazole using the agar dilution method. RESULTS: The highest resistance was observed to azithromycin (18%) followed by clindamycin (16%). Resistance to doxycycline and tetracycline was only found in two percent of the isolates and there was no resistance to trimethoprim/sulfamethoxazole and minocycline. Resistance to azithromycin and clindamycin was associated with acne severity (p=0.01 and p=0.03). Resistance to clindamycin was also statistically significantly higher in patients with a history of antibiotic therapy or concurrent antibiotic therapy during the study (p=0.04). CONCLUSION: To our knowledge, this is the first study documenting the susceptibility of C. acnes isolates to different antibiotics in Malta. Future research is needed to determine the clinical significance of antibiotic resistance of C. acnes.