The Gleason system for grading prostate cancer assigns a score on the basis of the most prevalent and second most prevalent grade. Several studies have investigated the clinical significance of a tertiary grade in radical prostatectomy samples. A systematic search of the published work identified seven studies that reported the prognostic value of a tertiary Gleason grade. Three studies correlated the presence of a tertiary grade with pathological stage, and six with prostate-specific antigen recurrence or clinical progression. In the small number of studies available, the frequency of a tertiary grade was consistently higher in samples characterised with pathological variables of poor outcome, such as extra-prostatic extension and positive surgical margins, but not lymph-node metastases. In five studies the presence of a tertiary grade increased the risk of prostate-specific antigen recurrence after radical prostatectomy by a factor of 2·5. However, modification of the Gleason score to include a tertiary grade in Gleason 4+3 tumours might overestimate the risk of seminal-vesicle or lymph-node invasion. This systematic review has established the association of a tertiary grade with poorer outcome than that associated with no tertiary grade. A tertiary grade should, therefore, be included in the pathological reporting of prostate cancer and be considered in the interpretation and design of clinical trials. However, all studies assessed for this review were retrospective, potentially affected by selection bias, and based on radical prostatectomy samples or transurethral resections rather than biopsy samples. Therefore, more evidence is needed to warrant the adaptation of the Gleason system to account for the presence of a tertiary grade, especially when scoring prostatic biopsies and applying predictive algorithms.