Patients with hypertrophic cardiomyopathy (HC) may present a wide spectrum of clinical and morphologic manifestations. Although many aspects of the natural history of HC are understood, the initial presentation and subsequent clinical course of certain subgroups are not yet well defined. To further our understanding in this regard, 241 middle-aged patients with HC (aged 35 to 55 years) were analyzed. The vast majority of patients (210) had already experienced symptoms, whereas the remaining 31 initially presented with no or minimal symptoms and are the focus of this investigation; 29 of these were followed for greater than or equal to 2 years (range to 11.5 years, mean 8). A separate group of 30 moderately symptomatic age- and gender-matched patients with HC were selected as control subjects for morphologic comparisons. Of the 29 study patients with follow-up, 22 (76%) are presently free of important cardiac symptoms, but 3 showed progression of symptoms, and 4 have died suddenly. Annual mortality rate was 1.7%. Eighteen of the middle-aged asymptomatic patients with HC (58%) had localized left ventricular hypertrophy, usually involving only the anterior ventricular septum; in contrast, only 9 of the 30 symptomatic control subjects (30%) had such localized hypertrophy (p = 0.02). In conclusion, of those patients with HC who achieved middle-age without developing important cardiac symptoms, approximately 75% remained asymptomatic during the ensuing average 8-year follow-up. However, such patients are not protected in absolute terms from unfavorable clinical events (despite relatively mild left ventricular hypertrophy and in most cases absence of outflow obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)