Reduced bone mineral density (BMD), osteopenia, and osteoporosis are slightly more common in patients with chronic lymphocytic leukemia (CLL). The risk of osteoporotic fractures in individuals with CLL is higher, than in healthy individuals of the same age. The mechanism underlying the CLL-associated BMD reduction can be related to decreased antioxidant protection and oxidative stress (OS). The study aimed to assess the relationship between oxidative stress, antioxidant protection, and osteopenia indicators in patients with CLL. Males aged 50–70 years were examined. Group 1 consisted of 14 healthy men, group 2 consisted of 54 patients with CLL having no BMD alterations, and group 3 consisted of 22 patients with CLL having signs of osteopenia. A densitometer was used to estimate BMD, T- and Z-scores of the lumbar vertebrae, proximal femoral neck (PFN), proximal femoral bone in all groups. At the beginning of the study, the levels of lipid peroxidation (LPO) products were determined in blood serum in all groups and bone tissue homogenate in groups 2 and 3; the total antioxidant status (TAS) was also determined. Bone densitometry indicators, serum LPO and TAS were assessed in all groups after 6 months of follow-up. At the beginning of the study osteopenia in PFN based on bone densitometry data was revealed in 29% of patients, while 6 months later osteopenia of all localizations was observed in 55% of patients. At the beginning of the study patients with CLL and osteopenia showed OS and reduced TAS in both blood serum and bone tissue. After 6 months patients with CLL and osteopenia showed signs of OS progression and TAS reduction. In patients with CLL, serum and bone tissue OS indicators are comparable and can be used to predict the onset of osteopenia within 6 months.