Background: This study investigates the predictive value of the systemic immune-inflammation index (SII), which was calculated as platelet × neutrophil/lymphocyte ratio, for all-cause mortality in patients with hypertrophic cardiomyopathy (HCM). Methods: A total of 360 HCM patients were enrolled. They were divided into three groups based on the tertiles of baseline SII. The association between SII and all-cause mortality was analyzed. Results: There were 53 HCM patients who died during a mean follow-up time of 4.8 years (min: 6 days and max: 10.8 years), and the mortality rate was 3.0 per 100 person years. The cumulative mortality rate was significantly different among the three tertiles of SII (P = 0.004), and the mortality rate in tertile 3 was much higher than that in the first two tertiles. In reference to tertile 1, the fully adjusted hazard ratios of all-cause mortality were 1.02 for the tertile 2 (95% confidence interval [CI]: 0.45–2.31, P = 0.966) and 2.31 for tertile 3 (95% CI: 1.10–4.87, P = 0.027). No significant interactions between SII and other variables were observed during subgroup analysis. The discriminative power was better for mid-term outcome than that for short-term or long-term outcomes. Sensitivity analyses including patients with normal platelet and white blood cell count have revealed similar results. Conclusion: SII was a significant risk factor for all-cause mortality in HCM patients. However, the discriminative power was poor to moderate. It could be used in combination with other risk factors in mortality risk stratification in HCM.