What is known and objective: Linezolid-induced thrombocytopenia is one of the many confounding conditions in critically ill patients. It is rare but prognostic importance of linezolid-induced thrombocytopenia in ICU population has not been well investigated. The study is to assess the incidence and risk factors of linezolid-induced thrombocytopenia in ICU patients. Methods: We conducted a retrospective study with ICU patients treated with linezolid between January 2005 and December 2015 at the adult medical, surgical, emergency, and neurological ICUs at 1500-bed tertiary university medical center. Results and discussion: There were 60 patients (mean age: 69.8 ± 11.9), 29 (48.3%) who developed linezolid-induced thrombocytopenia determined by the Naranjo algorithm on a case-by-case basis during the study period. The patients with linezolid-induced thrombocytopenia had a higher rate of any malignancy (41.4% vs 9.7%, P = 0.007), elevated baseline creatinine levels (median [interquartile range; IQR]: 1.7 mg/dL [0.9-2.5] vs 0.9 mg/dL [0.6-1.3]; P = 0.042), and lower baseline platelet counts (median [IQR] 160 × 109/L [128-230] vs 194 × 109/L [118-285]; P = 0.296) than patients without linezolid-induced thrombocytopenia. The patients who developed thrombocytopenia received more platelet transfusions (34.5% vs 6.5%, P = 0.009) and had higher ICU mortality rates (62.1% vs 32.3%, P = 0.037). Logistic regression analysis revealed the following significant risk factors for linezolid-induced thrombocytopenia: presence of any malignancy (odds ratio; OR [95% confidence interval; CI]: 8.667 [1.986-37.831]) and an elevated baseline serum creatinine level (OR: 1.673, CI: 1.046-2.675]). What is new and conclusion: Critically ill patients with any malignancy or an elevated baseline creatinine level who were treated with linezolid in the ICU were more likely to develop thrombocytopenia. More importantly, mortality increased with patients who developed linezolid-induced thrombocytopenia compared to those did not.