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Knowledge of etiology and timely treatment of underlying causes, when possible, play an important role in the successful therapy of patients with pyogenic liver abscess (PLA). Recent publications from Central Europe and Southeast Asia hint at considerable differences in etiology. In this article, we aim to elaborate these differences and their therapeutic implications. Apart from some special types of PLA that are comparable in Southeast Asia and Central Europe (such as posttraumatic or postprocedural PLA), there are clear differences in the microbiological spectrum, which implies different risk factors and disease courses. Klebsiella pneumoniae (K. pneumoniae) PLA is predominantly seen in Southeast Asia, whereas, in Central Europe, PLA is typically caused by Escherichia coli, Streptococcus or Staphylococcus, and these patients are more likely to be older and to have a biliary abnormality or malignancy. K. pneumoniae patients are more likely to have diabetes mellitus. Control of septic spread is crucial in K. pneumoniae patients, whereas treatment of the underlying diseases is decisive in many Central European PLA patients.