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<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The burden of non‐alcoholic fatty liver disease (NAFLD) in South America is among the highest in the world. However, the epidemiology and risk factors for NAFLD are insufficiently described in the region.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To explore the associations between clinical characteristics and histopathological features of NAFLD</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This was a descriptive study of 2722 patients with NAFLD from 8 medical centres across 5 South American countries. We collected clinical, biochemical and histopathological data using a templated chart. Fibrosis was assessed by elastography or fibrosis scores and confirmed with biopsy when available. We examined associations between histopathological features and clinical characteristics with logistic regression models. Models were adjusted for country, age and sex.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The median age was 53 years (IQR: 41–62), and 63% were women. Subjects from Brazil had the highest body mass index at 42 kg/m<jats:sup>2</jats:sup>. Sixty‐seven percent had dyslipidemia, 46% had obesity, 30% had hypertension, 17% had type 2 diabetes mellitus (T2DM) and 34% had metabolic syndrome. Biopsy reports were available for 948 (35%), of which 58% showed fibrosis, 91% steatosis and 65% inflammation; 25% showed significant fibrosis and 27% severe steatosis. Metabolic syndrome, T2DM and hypertension were significantly associated with significant fibrosis (OR = 1.94, <jats:italic>p</jats:italic> &lt; 0.001; OR = 2.93, <jats:italic>p</jats:italic> &lt; 0.001 and OR = 1.60, <jats:italic>p</jats:italic> = 0.003, respectively), severe steatosis (OR = 2.05, <jats:italic>p</jats:italic> &lt; 0.001; OR = 1.91, <jats:italic>p</jats:italic> = 0.001 and OR = 2.17, <jats:italic>p</jats:italic> &lt; 0.001, respectively) and liver inflammation (OR = 1.66, <jats:italic>p</jats:italic> = 0.007; OR = 2.00, <jats:italic>p</jats:italic> = 0.002; OR = 1.62, <jats:italic>p</jats:italic> = 0.001, respectively).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In the largest NAFLD cohort study to date from South America, metabolic syndrome, hypertension and T2DM were independently associated with significant fibrosis, severe steatosis, and inflammation. The prevalence of T2DM was lower than the reported global prevalence.</jats:p></jats:sec>