Background Thrombocytopenia in patients with myelofibrosis (MF) is prognostically detrimental and poses a therapeutic challenge. MF patients with thrombocytopenia are considered high‐risk by most prognostic models and their distinct phenotype has given rise to the emerging concept of cytopenic MF. Yet, the mechanisms underlying thrombocytopenia in MF are poorly understood. Methods This study aimed to highlight the genetic mechanisms driving low platelet counts in treatment‐naive MF patients, establish their phenotypic correlates, and assess prognostic factors specific to this group of patients. Results The authors found that most patients presenting with low platelets had a clear thrombocytopenia‐specific genetic abnormality involving a U2AF1 Q157 mutation, deletion 20q, molecular complexity (three or more mutations), or high‐risk karyotype. Etiologic clustering did not correlate with prognosis; however, thrombocytopenic patients were found to have unique prognostic variables including low serum albumin and mutations of SRSF2 and TP53. This led to the proposal of a prognostic model (SRSF2, albumin, TP53 score) that stratifies thrombocytopenic patients as low, intermediate, or high‐risk with corresponding median survivals of 93.5, 29.5, and 7.2 months, respectively. Conclusions This study demonstrates that thrombocytopenia in MF is driven by different genetic mechanisms and is not uniformly high‐risk. As novel agents with improved hematologic safety profiles enter the treatment landscape, thoughtful, risk‐adapted therapeutic decisions will be required for MF patients with thrombocytopenia. Lay Summary A significant minority of patients with myelofibrosis (MF) present with low platelets. Historically, these patients have been viewed as having “high‐risk” disease, but this may not be uniformly true. Our study shows that there are various different causes for low platelets in MF, some of which represent high‐risk disease whereas others do not. Additionally, our study shows that genetic mutations affecting the genes SRSF2 and TP53 are uniquely problematic in this group, as is a low serum albumin level. This study helps to risk‐stratify MF patients with thrombocytopenia, thereby providing more information to guide informed and individualized treatment decisions. Cytopenic myelofibrosis (MF) is emerging as a distinct phenotypic entity that poses unique therapeutic challenges; however, little is known about the various causes of thrombocytopenia in MF and factors that influences prognosis in this subgroup. With the recent and upcoming approval of new, less myelosuppressive treatment options, it will be vital to understand how to risk stratify thrombocytopenic MF patients in an effort to individualize therapy.