We sought to evaluate the adverse effect profile of linezolid among thermal injury patients requiring treatment for Enterococcus species or other Gram-positive infection warranting treatment with linezolid. Seventy-six inhalation injury and/or thermal injury patients experiencing 94 exposures to linezolid for 48 hours or longer (range, 2-83 days) were included. We evaluated leukocyte count and platelet count for the time period preceding, during, and after therapy with linezolid based on specified time periods of exposure for evaluation of specific adverse effects. Sixty-three of 76 (83%) patient admissions were complicated by inhalation injury. The average TBSA involvement was 34.4% (range, 0-98%). The onset of thrombocytopenia before linezolid therapy was noted in 21 of 57 patients (36.8%), which was attributable to fluid resuscitation and acute platelet consumption. After they were exposure to linezolid, 12 patients developed thrombocytopenia. Platelet counts recovered in 7 of these 12 patients with continued exposure to linezolid; however, thrombocytopenia persisted for more than 9 days after therapy in 9 patients, of whom 6 patients succumbed to sepsis. On average, thrombocytes increased by 102,000/mm3 during linezolid treatment. Leucopenia was rare in thermal injury patients, and persisting thrombocytopenia in this population was associated with sepsis and mortality. Continuing linezolid therapy after the onset of thrombocytopenia among survivors almost always resulted in recovery from thrombocytopenia.