The accumulation of independent mutations in two populations of an ancestral species over time often leads to reproductive isolation. Reproductive isolation between diverging populations is re-enforced by genetic mating barriers that occur either pre- or post-zygotically. Hybrid sterility is the most common form of post-zygotic isolation in plants. Four post-zygotic sterility loci have been recently cloned in Oryza sativa, Sa, s5, DPL1 and DPL2; these loci explain, in part, the limited hybridization that occurs between the domesticated cultivated rice varieties, O. sativa spp. japonica and O. sativa spp. indica. In the United States, cultivated fields of japonica rice are often invaded by conspecific weeds that have been shown to be of indica origin. Crop-weed hybrids have been identified in crop fields, but at low frequencies. This study aimed to examine the role of these known hybrid incompatibility loci in the interaction between cultivated and weedy rice, and further assess the evolutionary processes acting at these loci. We identified a novel neutral allele at Sa, designated SaFX, that seemingly acts to restore fertility. Additionally, we found a strikingly high frequency of neutral-type alleles in weedy populations at multiple loci, suggesting that weedy individuals, particularly those of the SH and BRH groups, should be able to freely hybridize with the local japonica crop.