ObjectiveTo systematically review the adverse drug reactions (ADRs) caused by piperacillin. MethodsPubMed, EMbase, Web of Science, CNKI, WanFang Data and VIP databases were electronically searched to collect case reports on ADRs caused by piperacillin from inception to December 31, 2021. Two reviewers independently screened literature, extracted data and then a qualitative systematic review was performed. ResultsA total of 168 case reports involving 170 patients were included. The male to female ratio was 1.06∶1, and the median age was 54 year old. The statistical results showed that ADRs caused by piperacillin mostly involved the whole body (n=55), followed by the blood system (n=48), skin and soft tissue system (n=39) and nervous system (n=18). The most frequently reported cases were anaphylactic shock (n=29), followed by drug fever (n=19), rash (n=17) and thrombocytopenia (n=15). The most serious ADRs were anaphylactic shock (n=29) and bullous epidermal necrolysis (n=6). ConclusionCurrent evidence shows that ADRs caused by piperacillin mostly involved the whole body and the most serious ADRs are toxic epidermal necrolysis and anaphylactic shock.