Endophenotypes are intermediate phenotypes on the putative causal pathway from genotype to phenotype and can aid in discovering the genetic etiology of a disorder. There are currently very few suitable endophenotypes available for substance use disorders (SUD). The amplitude of the P300 event-related brain potential is a possible candidate. The present study determined whether the P300 amplitude fulfils two fundamental criteria for an endophenotype: (1) an association with the disorder (disease marker), and (2) presence in unaffected biological relatives of those who have the disorder (vulnerability marker). For this purpose, two separate meta-analyses were performed. Meta-analysis 1 investigated the P300 amplitude in relation to SUD in 39 studies and Meta-analysis 2 investigated P300 amplitude in relation to a family history (FH+) of SUD in 35 studies. The findings indicate that a reduced P300 amplitude is significantly associated with SUD (d =0.51) and, though to a lesser extent, with a FH+ of SUD (d =0.28). As a disease maker, the association between reduced P300 amplitude and SUD is significantly larger for participants that were exclusively recruited from treatment facilities (d =0.67) than by other methods (i.e., community samples and family studies: d =0.45 and 0.32, respectively), and larger for abstinent SUD patients (d =0.71) than for current substance users (d =0.37). Furthermore, in contrast to FH+ males, a P300 amplitude reduction seems not to be present in FH+ females (d =-0.07). Taken together, these results suggest that P300 amplitude reduction can be both a useful disease and vulnerability marker and is a promising neurobiological endophenotype for SUD, though only in males. Implications and future directions are discussed. (C) 2011 Elsevier Ltd. All rights reserved.