Penicillium marneffei is a rare deep tissue fungal infection causing an endemic in Southeast Asia. This infection causes penicilliosis disease and is more common in patients who are immunocompromised. To date, no cases of P. marneffei infection relapse following treatment have been reported. A 36-year-old patient attended our hospital as a result of intermittent fever, cough, shortness of breath and multiple soft lesions located on the face, arms, neck and trunk. The medical radiological examination of the lung revealed multiple patchy exudative shadows, thick-walled hollow inner part of the visible lesions, bilateral pleural and pericardial effusion. Assessing the skull and right collarbone, bilateral thoracic ribs and a plurality revealed numeorus lesions with reduced bone destruction and revealed that the patient was positive for P. marneffei infection. After 6 months of antifungal therapy, pulmonary symptoms and the surface lesions of the patient rapidly disappearance and the physical condition markedly improved. The patient did not attend a follow-up and stopped antifungal treatment. In February 2016, the patient presented with left breast and subcutaneous soft tissue mass of the head and neck. Fungal culture results revealed that the patient was again positive for P. marneffei infection. The present case suggested that clinical doctors and patients must pay more attention to regular treatment of the disseminated P. marneffei. It also highlighted the requirement for awareness of penicilliosis in non-acquired immune deficiency syndrome patients, who are not immunocompromised, who are living in or traveling to P. marneffei-endemic areas.