Background: Due to the contradictory results of the effects of Vitamin B6 in reducing the hematotoxic effects of linezolid, the present study aimed to investigate the possible role of Vitamin B6 administration in reducing linezolid-related hematological toxicities in patients with chronic osteomyelitis. Materials and Methods: In a randomized double-blind placebo-controlled clinical trial, patients with chronic osteomyelitis were randomly divided into two groups (n = 40 each): the intervention group received Vitamin B6 40 mg twice daily from the beginning of treatment with linezolid and the control group received placebo with linezolid, both for 21 days. Blood variables including hemoglobin (Hb), white blood cells (WBC), and platelets (PLT) were measured at baseline and at the end of the 1st, 2nd, and 3rd weeks (days 7, 14, and 21) of the intervention. Results: There was no significant difference between the groups regarding the count of WBC and PLT and level of Hb at evaluated time points. Furthermore, there was a significant decreasing trend in all parameters within both groups; however, the decreasing trend of both PLT and WBC was slower in the intervention (Vitamin B6) group compared to the placebo group. Conclusion: Vitamin B6 has no significant effect in the reduction of hematological adverse effects of linezolid in chronic osteomyelitis patients. However, it could retard the decreasing trend of WBC and PLT counts.