Distinguishing amoebic from pyogenic liver abscesses is crucial because their treatments and prognoses differ. We retrospectively reviewed the medical records of 577 adults with liver abscess in order to identify clinical, laboratory, and radiographic factors useful in differentiating these microbial aetiologies. Presumptive diagnoses of amoebic (n = 471; 82%) vs. pyogenic (n = 106; 18%) abscess were based upon amoebic serology, microbiological culture results, and response to therapy. Patients with amoebic abscess were more likely to be young males with a tender, solitary, right lobe abscess (P = 0.012). Univariate analysis found patients with pyogenic abscess more likely to be over 50 years old, with a history of diabetes and jaundice, with pulmonary findings, multiple abscesses, amoebic serology titres <1:256 IU, and lower levels of serum albumin (P < 0.04). Multivariate logistic regression analysis confirmed that age >50 years, pulmonary findings on examination, multiple abscesses, and amebic serology titres <1:256 IU were predictive of pyogenic infection. Several clinical and laboratory parameters can aid in the differentiation of amebic and pyogenic liver abscess. In our setting, amebic abscess is more prevalent and, in most circumstances, can be identified and managed without percutaneous aspiration.