Abstract: This study examined the efficacy, safety and cost-effectiveness of administering antibiotic prophylaxis prior to endodontic procedure in an effort to clarify the 2007 IE prevention guidelines. Methods A non-parametric, meta-analysis of studies reporting antibiotic efficacy was executed. Antibiotic safety analysis was reported as IE cases prevented compared with antibiotic-associated deaths per 10 million patients receiving prophylaxis. Cost-effective analysis was reported in Quality Adjusted Life Years (QALY). No data exists demonstrating that a decreased frequency of bacteremias confers an IE prevention benefit. The pooled adjusted Odds Ratio (OR) for the development of IE with antibiotic prophylaxis among the four case-control studies was highly heterogenous and statistically non-significant (0.48 [95% CI (0.2-1.16) p-value = 0.10]). Chemoprophylaxis utilizing amoxicillin or ampicillin presents a higher risk of fatal adverse drug reactions (20 cases per 1 million patients treated) then cephalosporin, macrolide and clindamycin regimens (0.5-5.7 cases per 10 million patients treated). IE chemoprophylaxis to moderate-risk patients costs, on average $96,174 per QALY saved, exceeding the cost-effectiveness threshold. Oral chemoprophylactic therapy to high-risk patients is a cost-effective practice with an average cost of $29,290 per QALY. The AHA, 2007 IE prevention guidelines appropriately reflect the efficacy, safety and cost-effective evidence for IE prophylaxis. Antibiotic administration to moderate and high-risk patients prior to endodontic procedure provides minimal to no protective efficacy. The administration of oral chemoprophylaxis prior to endodontic procedure only to patients with a high-risk of adverse outcomes subsequent to the acquisition of IE is a beneficial, safe and cost-effective practice.