Many patients with chronic lymphocytic leukemia (CLL) experience physical dysfunction and low overall fitness. It remains unknown what factors drive CLL physical dysfunction. We assessed physical function and metabolic lipoprotein panels in 106 patients with CLL. In univariate analyses of clinical factors, a longer time since diagnosis was associated with a higher likelihood of dysfunctional aerobic fitness (OR = 3.56, 95% CI: 1.37-9.22; p = 0.002) and physical performance (SPPB: OR = 2.03, 95% CI: 1.20-3.44; p = 0.004). Having received treatment was associated with a higher likelihood of dysfunctional aerobic fitness (OR = 1.57, 95% CI: 1.02-2.40; p = 0.036), SPPB (OR = 1.85, 95% CI: 1.13-3.03; p = 0.011) and grip strength (OR = 1.67, 95% CI: 1.10-2.55; p = 0.015). We found that several small HDL particle parameters, higher levels of citrate (OR = 2.01, 95% CI: 1.22-3.31; p = 0.030), and lower levels of hemoglobin (OR = 0.50, 95% CI: 0.31-0.82; p = 0.030) were associated with a higher likelihood of dysfunctional aerobic fitness. Multivariable least absolute shrinkage and selection operator (LASSO)-penalized regression analyses using variable importance measures (VIM) showed that 7.8-nm HDL particles (VIM = 1.000) and total HDL particle levels (VIM = 1.000) were more informative than clinical measures for the odds of dysfunctional aerobic fitness and 6-min walk functional fitness, respectively, while 10.3-nm HDL particles (VIM = 0.383) were more informative for grip strength. Time since diagnosis (VIM = 0.680) and having received treatment (VIM = 0.490) were more informative than lipoprotein measures for the odds of having dysfunctional SPPB. Taken together, we establish significant relationships between clinical and metabolic factors and physical characteristics that might prompt early use of ancillary support services.