Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder manifesting as cardiac hypertrophy with myocyte disarray and an increased risk of sudden death^1,2. Mutations in five different loci cause FHC and 3 disease genes have been identified: β cardiac myosin heavy chain³, α tropomyosin and cardiac troponin T^4,5. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sar-comere components⁴. Two further FHC loci have been mapped to chromosomes 11p13–q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11 p11.2 and proposed as a candidate FHC gene⁸. Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments. Phosphorylation of MyBP-C appears to modulate contraction^8–10. We report that cardiac MyBP-C is genetically linked to CMH4 and demonstrate a splice donor mutation in one family with FHC and a duplication mutation in a second. Both mutations are predicted to disrupt the high affinity, C-terminal, myosin-binding domain of cardiac MyBP-C. These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11 p and reaffirm that FHC is a disease of the sarcomere.