Myocardin is thought to contribute to heart hypertrophy as assessed in animal models. The aim of this study was to identify polymorphisms on the myocardin gene and investigate possible relationships with left ventricular structure in human hypertrophic cardiomyopathy (HCM). Eighty‐four native Cretan individuals (36 patients with HCM and 48 healthy controls) were examined by direct sequencing and subsequent restriction fragment length polymorphism analysis and six polymorphisms were identified in the promoter region at positions −435T>C (rs758187), −629A>T (rs8071072), −1030C>G (rs1233851), −1069A>G, −1166A>G and −1406G>A (rs976906). Allele and haplotype frequencies were not significantly different between patients and controls. However, patients carrying the [−435C;−629T] allelic variant had decreased left ventricular wall thickness (LVWT, p = 0.020) and left ventricular mass (p = 0.006) as compared with the wild‐type genotype. Carrier status of this myocardin promoter allelic variant was also associated with significant lower myocardin mRNA levels in peripheral blood (p = 0.039). Thus, a myocardin promoter allelic variant existing in the normal Cretan population was associated with decreased left ventricular mass in HCM patients and decreased myocardin mRNA levels in peripheral blood. Our results may be limited by the limited sample size, but are strengthened by the genetic homogeneity of the Cretan population. Our data suggest that functional natural myocardin promoter variation might be a genetic factor contributing to inter‐individual differences in the development of cardiac hypertrophy.