B30.2 domains, also known as PRY/SPRY, are key components of specific subsets of two large families of proteins involved in innate immunity: the tripartite motif proteins (TRIMs) and the Nod-like receptors (NLRs). TRIM proteins are important, often inducible factors of antiviral innate immunity, targeting multiple steps of viral cycles through a variety of mechanisms. NLRs prime and regulate systemic innate defenses, especially against bacteria, and control inflammation. Large TRIM and NLR subsets characterized by the presence of a B30.2 domain have been reported from a few fish species including zebrafish and seem to be strongly prone to gene duplication/expansion. Here, we performed a large-scale survey of these receptors across about 150 fish genomes, focusing on ray-finned fishes. We assessed the number and genomic distribution of domains and domain combinations associated with TRIMs, NLRs, and other genes containing B30.2 domains and looked for gene expansion patterns across fish groups. We then used a model to test the impact of taxonomy, genome size, and environmental variables on the copy numbers of these genes. Our findings reveal novel domain structures, clade-specific gains and losses. They also assist with the timing of the gene expansions, reveal patterns associated with the MHC, and lay the groundwork for further studies delving deeper into the forces that drive the copy number variation of immune genes on a species level.