Pyoderma gangrenosum is a rare and severe inflammatory skin condition. There are different variants, including generalised and atypical forms, but the most common presentation is an enlarging ulcer on the lower extremities. Treatment can represent a challenge for physicians and there are no guidelines based on randomised controlled trials. We report an exceptional case of widespread and refractory pyoderma gangrenosum in a middle-aged woman where cocaine use may have played a role. Treatment with i.v. pulse corticosteroids and cyclosporine was ineffective, and disease control was obtained with oral corticosteroids together with mycophenolic acid, infliximab and abstinence from cocaine consumption. There was a temporal relationship between disease outbreaks and cocaine consumption and improvement after its discontinuation. In the present case such clinical severity without associated pathology and the temporal association with cocaine abuse raises the possibility of cocaine playing an aetiological role as well as accounting for therapy resistance.