This case contemplates the unusual presentation, challenging diagnostic workup and conservative therapeutic process of a patient with Actinomyces empyema complicated along the way due to drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. The patient was a 40-year-old male, who presented with pleurodynia and fever. Laboratory exams showed elevated inflammatory markers and imaging revealed two biconvex fluid pockets located in the right lower lobe, from which the fluid was positive for Actinomyces meyeri. The initial conservative process with intravenous antibiotics and successful drainage with intrapleural fibrinolysis improved our patient. However, after a few days, the patient’s fevers relapsed, and as regress of the empyema was discussed as a complication, he developed a maculopapular symmetrical rash of the trunk and legs accompanied by enlarged lymph nodes, eosinophilia, thrombocytopenia, and atypical lymphocytes. The diagnosis of DRESS syndrome due to antibiotic therapy for actinomyces empyema was established and a balance between bactericidal and immunosuppression medication had to be found. Fortunately, the patient withstood prolonged antibiotic therapy and got fully treated without any relapses.