In situations where acne has proved resistant to other systemic agents or they are not indicated and isotretinoin is not desired by patients, the authors find amoxicillin, TMP-SMX, and spironolactone, alone or in combination, useful alternatives. In women who have acne, spironolactone can be used, and in patients who have sulfa allergy, amoxicillin can be used. It is important to continue alternate topical therapy along with these interventions to augment the improvement and to assist in the eventual discontinuance of oral medication. All of the authors' patients were using topical therapy concomitantly and, although this may have contributed to improvement, the authors believe the addition of amoxicillin, TMP-SMX, or spironolactone contributes to the majority of improvement. Tetrospective chart analysis provides supportive data for amoxicillin, TMP-SMX, and spironolactone in the treatment of refractory acne vulgaris.