Abstract: Objective To evaluate the effect of chlorophosphonate liposomes (CL) on pain and anxiety behaviors in a chemotherapy-induced peripheral neuropathy (CIPNP) model of mice and explore the underlying mechanisms. Methods Male C57BL/6J mice were randomly divided into three groups: a control+ blank liposome (Control+BL) group, a CIPNP+blank liposome (CIPNP+BL) group, and a CIPNP + chlorophosphonate liposome (CIPNP+CL) group. The CIPNP model was established by intraperitoneal injection of paclitaxel. On post-modeling day 9, the modeled mice received 200 μl of CL at 5 g/L through intraperitoneal injection, while mice in the Control+BL group were given an equal volume of normal saline and BL. The 50% mechanical withdrawal threshold (50% MWT) and thermal withdrawal latency (TWL) were measured to assess the effect of CL on pain thresholds in CIPNP mice. The open field test and elevated plus-maze test were used to evaluate the effect of CL on anxiety-like behaviors in CIPNP mice. The changes in the number of macrophages in the dorsal root ganglia (DRG) of the mice were measured by immunofluorescence staining. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the DRG were analyzed by Western blot. Results Compared with the CIPNP + BL group, the CIPNP + CL group showed increases in 50% MWT and TWL, and the percentage of time spent in the center area of the open field and the open arms of the elevated plus maze. The CIPNP+CL group also presented a reduced number of macrophages and decreased levels of TNF-α, IL-1β, and IL-6 in the DRG, compared the CIPNP+BL group (P<0.05). Conclusions CL alleviates pain-anxiety comorbidities induced by paclitaxel in mice, possibly by clearing macrophages in the DRG and reducing the release of pro-inflammatory factors TNF-α, IL-1β, and IL-6.