Acute pain is among the most common reasons that people consult primary care physicians, who must weigh benefits versus risks of analgesics use for each patient. Paracetamol (acetaminophen) is a first-choice analgesic for many adults with mild to moderate acute pain, is generally well tolerated at recommended doses (≤4 g/day) in healthy adults and may be preferable to non-steroidal anti-inflammatory drugs that are associated with undesirable gastrointestinal, renal, and cardiovascular effects. Although paracetamol is widely used, many patients and physicians still have questions about its suitability and dosing, especially for older people or adults with underlying comorbidities, for whom there are limited clinical data or evidence-based guidelines. Inappropriate use may increase the risks of both overdosing and inadequate analgesia. To address knowledge deficits and augment existing guidance in salient areas of uncertainty, we have researched, reviewed, and collated published evidence and expert opinion relevant to the acute use of paracetamol by adults with liver, kidney, or cardiovascular diseases, gastrointestinal disorders, asthma, or/and who are older. A concern is hepatotoxicity, but this is rare among adults who use paracetamol as directed, including people with cirrhotic liver disease. Putative epidemiologic associations of paracetamol use with kidney or cardiovascular disease, hypertension, gastrointestinal disorders, and asthma largely reflect confounding biases and are of doubtful relevance to short-term use (<14 days). Paracetamol is a suitable first-line analgesic for mild to moderate acute pain in many adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, and/or who are older. No evidence supports routine dose reduction for older people. Rather, dosing for adults who are older and/or have decompensated cirrhosis, advanced kidney failure, or analgesic-induced asthma that is known to be cross-sensitive to paracetamol, should be individualized in consultation with their physician, who may recommend a lower effective dose appropriate to the circumstances.