Introduction: Research about the risk factors associated with community-acquired acute kidney injury (CA-AKI) in acute medical diseases is scarce. Data extrapolation from surgical to medical illnesses is questionable. Objectives: To evaluate potential risk factors and hospital outcomes associated with a CA-AKI in medical illnesses. Methods: We performed an unmatched nested case-control study from a previous prospective cohort study. We included adult patients with acute illnesses treated with internal medicine. Cases were defined as patients with a CA-AKI diagnosis upon hospital admission, and controls included patients from the same cohort who did not develop AKI during the first 5 days of hospitalisation. A logistic regression model was used to assess the association between potential risk factors and CA-AKI. Results: A total of 868 patients were included in the study (223 cases and 645 controls). The median age was 65 years (interquartile range 50–78). In a logistic regression model, the risk factors associated with CA-AKI included chronic kidney disease (CKD; OR 6.27; 95% CI 2.95–13.3, p < 0.001), ≥65 years old (OR 1.72; 95% CI 1.16–2.57, p = 0.007), acute bacterial infection (OR 1.95; 95% CI 1.36–2.80, p < 0.001), hypovolaemia (OR 1.88; 95% CI 1.32–2.69, p < 0.001), pre-hospital nephrotoxic drugs (OR 1.77; 95% CI 1.23–2.55, p = 0.002), anaemia (OR 1.49; 95% CI 1.03–2.14, p = 0.031) and systolic blood pressure (SBP) <107 mm Hg (OR 2.25; 95% CI 1.38–3.67, p = 0.001). A significant interaction between CKD and age was found ( p = 0.017) and included in the model (patients with CKD and ≥65 years old [OR 10.85; 95% CI 4.14–28.41, p < 0.001]). The area under the receiver operating characteristic curve of the final model was 0.743. Conclusions: CKD is strongly associated with CA-AKI upon hospital admission in medical illnesses patients. Older age enhances the risk of CA-AKI in patients with CKD. Other risk factors include pre-hospital nephrotoxic drugs, acute bacterial infection, anaemia, low SBP and hypovolaemia.