Minocycline, a semisynthetic derivative of tetracycline, has become a commonly prescribed medication for the treatment of persistent acne. It has been associated with a variety of adverse reactions, including one published case of serum sickness. We describe two additional cases of serum sickness reactions due to minocycline, characterized by erythematous rash, arthropathy, and in one case, angioedema. Both patients recovered fully after treatment with an antihistamine in combination with a brief course of corticosteroids. Although these represent only the second and third cases in the literature of minocycline-induced serum sickness, it may be reported more frequently in the future with the increased use of minocycline.