The optimal hemoglobin level in patients with hypertension or heart failure is not yet defined. The aim of the present investigation was to examine the relation of hemoglobin with cardiovascular outcomes in high-risk patients with isolated systolic hypertension (ISH) and left ventricular hypertrophy (LVH). In 1326 patients with ISH in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, hemoglobin and cardiovascular outcomes were examined using Cox proportional hazard models. Baseline hemoglobin was negatively related to the rate of cardiovascular death (hazard ratio 0.81 [95% CI 0.67-0.98] per 1 g/dL, p = 0.032) after adjusting for baseline Framingham risk score (FRS), LVH, treatment, and estimated glomerular filtration rate (eGFR). Hemoglobin decreased slightly during the study and the decline was more pronounced in the losartan group (13.9 ± 1.3 g/dL to 13.6 ±1.4 g/dL) than in the atenolol group (13.9 ± 1.2 g/dL to 13.8 ± 1.4 g/dL). Hemoglobin as a time-varying covariate was negatively associated with the rate of cardiovascular death (hazard ratio 0.75 [0.63-0.90], p < 0.001) and stroke (hazard ratio 0.84 [0.72-0.99], p = 0.040), after adjusting for baseline FRS, LVH, treatment, and eGFR. In conclusion, in this high-risk population with ISH and LVH, lower hemoglobin at baseline was associated with higher probability of cardiovascular death, and fall in hemoglobin over time was associated with higher probability of cardiovascular death or stroke and this effect was attenuated by treatment with losartan.