An observer-blind comparative clinical study was carried out in 108 patients presenting with ankle sprains at an Accident and Emergency department. The efficacy and tolerability of diclofenac potassium (50 mg 3-times daily) was compared with that of piroxicam (20 mg once daily), and placebo. Patients were allocated at random to receive one or other of the three treatments for 7 days. There were 36 patients in each group. The analgesic and anti-inflammatory effects of treatment were assessed from volumetric measurements of inflammation at the injured ankle, tenderness, pain on passive movement, severity of the joint lesion, severity of pain at rest and on movement. The overall reductions in pain and inflammation were assessed at the end of the study. The results in patients treated with diclofenac potassium were significantly better than those in patients treated with piroxicam with respect to the improvement in pain on walking and the overall reduction in pain and inflammation, and both active treatments were superior to placebo. There was no significant difference between diclofenac potassium and piroxicam with respect to inflammation measured by volumetry, tenderness, and severity of pain at rest, but both active treatments were consistently superior to placebo. No serious adverse effects were reported. All the patients treated with diclofenac potassium and all those treated with piroxicam said that they would be willing to take the drug again; this was the case with only 27.8% of the placebo group. Diclofenac potassium can be considered an effective treatment for acute ankle sprains with a rapid onset of analgesic and anti-inflammatory action and good tolerability.