The recent US Food and Drug Administration approval of pivmecillinam-an oral prodrug of the amidinopenicillin antibiotic mecillinam-presents a valuable opportunity to address the need for new treatments for uncomplicated urinary tract infection (uUTI). We report findings of a systematic literature review of the safety profile of pivmecillinam/mecillinam based on more than 40 years' experience, mainly in Europe and Canada, to describe its tolerability profile and identify any important safety signals. In total, 110 eligible publications were identified describing use of pivmecillinam/mecillinam as monotherapy or in combination, for treatment of uUTI or other infectious conditions. These studies revealed a benign safety and tolerability profile, awareness of which will inform treatment decisions as pivmecillinam is made available in the United States. Together with the evidence for efficacy of, and minimal resistance to, pivmecillinam, the findings of this review support the position of pivmecillinam as a first-line treatment for uUTI.