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Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following commencement of treatment. However, it remains unknown whether higher fitness in CLL patients provides anti-oncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naïve CLL patients from 144 CLL patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p=0.003), Day 4 (p=0.001) and Day 5 (p=0.009). No differences between groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between groups. Of these, 14 miRNAs had ≤-1 or ≥1 log2 fold differences. CLL-FIT patients had 5 exosomal miRNAs with lower expression and 9 miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all pneg (p=0.015 and p=0.014) and higher frequencies of NKG2Aneg/CD158b+ mature NK-cells (p=0.047). Absolute numbers of lymphocytes including CD19+/CD5+ CLL-cells were similar between groups (p=0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro, and with altered circulating and cellular factors indicative of better immune functions and tumor control.