The Cochrane Systematic Review promotes evidence-based outcomes studies. The review summarized here was conducted in an attempt to achieve reliable evidence concerning the effectiveness, or otherwise, of prescribing antibiotics for patients having irreversible pulpitis. A competent search strategy was developed and used across several databases including MEDLINE to identify randomized controlled trials for inclusion. Assessment of methodological quality was based on criteria defined by The Cochrane Collaboration. Clinical outcome, expressed in terms of pain relief, was examined. There was a relative dearth of research providing a high level of evidence. Only one methodologically sound trial was found that compared pain relief with systemic antibiotic/analgesic treatment against a placebo/analgesic combination during the acute preoperative phase of irreversible pulpitis. Although the selected study used a relatively small, low-powered sample, it did provide some evidence that there is no significant difference in pain relief for patients with untreated irreversible pulpitis who received antibiotics versus those who did not. These findings increase the rationale to investigate the teaching of safe and effective antibiotic prescribing in endodontics and to advance the development of appropriate evidence-based clinical guidelines.