Abstract  Pathological left ventricle (LV) hypertrophy (LVH) results in reactive and replacement fibrosis. Volume overload LVH (VOH) is less profibrotic than pressure overload LVH (POH). Studies attribute subendocardial fibrosis in POH to ischemia, and reduced fibrosis in VOH to collagen degradation favoring dilatation. However, the mechanical origin of the relative lack of fibrosis in VOH is incompletely understood. We hypothesized that reduced ischemia propensity in VOH compared to POH accounted for the reduced replacement fibrosis, along with reduced reactive fibrosis. Rats with POH (ascending aortic banding) evolved into either compensated‐concentric POH (POH‐CLVH) or dilated cardiomyopathy (POH‐DCM); they were compared to VOH (aorta‐caval fistula). We quantified LV fibrosis, structural and hemodynamic factors of ischemia propensity, and the activation of profibrotic pathways. Fibrosis in POH‐DCM was severe, subendocardial and subepicardial, in contrast with subendocardial fibrosis in POH‐CLVH and nearly no fibrosis in VOH. Propensity for ischemia was more important in POH versus VOH, explaining different patterns of replacement fibrosis. LV collagen synthesis and maturation, and matrix metalloproteinase‐2 expression, were more important in POH. The angiotensin‐II‐transforming growth‐factor ß axis was enhanced in POH, and connective tissue growth factor (CTGF) was overexpressed in all types of LVH. LV Resistin expression was markedly elevated in POH, mildly elevated in VOH and independently reflected chronic ischemic injury after myocardial infarction. In vitro, resistin is induced by angiotensin‐II and induces CTGF in cardiomyocytes. Based on these findings, we conclude that reduced ischemia propensity and attenuated upstream reactive fibrotic pathways account for the attenuated fibrosis in VOH versus POH. This article is protected by copyright. All rights reserved