Staphylococcus simulans is a coagulase-negative organism, mainly an animal pathogen. Reports of human infection have been infrequent, mainly in patients with repeated animal contact. We report the first case of pleural empyema in an elderly woman. S. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters. The challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself. Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. Staphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate. Despite aggressive treatment, the patient succumbed to her illness.