Background: Women with multifocal or multicentric breast tumors (multifocality henceforth) have been reported to have greater probability of nodal metastasis and relapse and worse survival than women with unifocal tumors. However, these associations have been inconsistent and multifocality is not taken into account by staging guidelines and prognostic models. Methods: A systematic review of Medline and EMBASE (host: Ovid) from 1946 to July 2013 identified publications exploring the association between multifocality and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS) and loco-regional relapse (LRR). The hazard ratios (HR) for OS and DFS for multifocal compared to unifocal tumors were extracted from multivariable analyses and included in a meta-analysis. For studies not reporting multivariable analyses, odds ratios (OR) were estimated from Kaplan-Meier curves for all endpoints at 5 and 10 years. Results: Twenty-two studies comprising 67,557 women were included. Multifocality was reported in 9.5% of patients. Classical prognostic factors were well balanced between unifocal and multifocal populations. In multivariable analyses, multifocality was associated with significantly worse OS (HR=1.65, p=0.02), and a non-significant association with worse DFS (HR=1.96, p=0.07). Inter-study heterogeneity was significant (Cochran Q p<0.001 in both analyses). Similar results were observed for the odds of death or disease recurrence by 5 years (OR=1.39, p=0.02; OR=1.52, p=0.02, respectively). Additionally, multifocality was associated with worse DSS and a higher odds of LRR (OR=1.56, p=0.03; and OR=3.23, p=0.02, respectively). Similar estimates were observed at 10 years but statistical significance was only reached for DSS and LRR (OS: OR=1.40, p=0.07; DFS: OR=1.49, p=0.06; DSS: OR=1.69, p<0.001; LRR: OR=2.94, p=0.03). Conclusions: Multifocality appears to be associated with a worse prognosis. Substantial inter-study heterogeneity limits the precise determination of increased risk; however, the inclusion of multifocality as an independent prognostic factor appears warranted.