Introduction: When bacterial pericarditis is suspected, urgent pericardial drainage combined with intravenous antibacterial therapy is mandatory to avert devastating, life-threatening complications. There have been scanty results on antimicrobial susceptibility of common causative microorganisms of bacterial pericarditis; most studies had small sample sizes and were performed decades ago. Methodology: This prospective study surveyed the causative bacteria in infectious pericardial effusions and their antimicrobial susceptibility among 320 consecutive cardiac patients who underwent pericardiocentesis at Tehran Heart Center between 2007 and 2012, using the European Society of Cardiology (ESC)'s criteria. Results: Staphylococcus spp. (S. epidermidis, S. aureus, S. haemolyticus) were the main causative organisms isolated from cultures of pericardial effusion samples. Other causative organisms were Streptococcus spp., Enterococcus faecium, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the cultures studied, 35% methicillin-resistant Staphylococcus epidermidis (MRSE) and 42.9% methicillinresistant Staphylococcus aureus (MRSA) were detected. The most effective antimicrobial agents in S. epidermidis were gentamicin, ciprofloxacin, and cefoxitin. Clindamycin was relatively effective. S. aureus was highly susceptible to clindamycin and erythromycin. In cases of S. haemolyticus infection, clindamycin, erythromycin, cefoxitin, and ciprofloxacin were effective antibiotics. Conclusions: In order to diminish the nascence and extension of antimicrobial-resistant pathogens, logical and optimized antimicrobial usage and monitoring in hospitals are highly recommended. It is incumbent on healthcare systems to determine current local resistance patterns by which to guide empiric antimicrobial therapy for specific infections and microorganism types.