We studied 54 patients with hypoxemic chronic obstructive pulmonary disease (COPD). The Mini Mental State Examination and the Mental Deterioration Battery were used for neuropsychological assessment. Heart rate variability (HRV) was assessed based on 24-h Holter ECG recording. Mann-Whitney test was used to compare HRV parameters of patients performing normally or abnormally on individual neuropsychological tasks. Spearman's rho was used to investigate the correlations between HRV parameters and neuropsychological scores, indexes of health status or COPD severity. Patients with defective performance at copying drawings with landmarks (CDL) test (N = 23) had lower very low frequency (VLF) power with respect to patients with normal performance (N = 31) (24 h: median 213; interquartile range 120-282 vs. 309; 188-431 ms2, p = 0.043; daytime: 202; 111-292 vs. 342; 194-397 ms2, p = 0.039). The CDL score correlated with the VLF power (24 h: rho = 0.27, p = 0.049; daytime: rho = 0.30, p = 0.028), and the normalized low frequency/high frequency (LF/HF) ratio (24 h: rho = 0.27, p = 0.05; daytime: rho = 0.33, p = 0.015). Sympathetic modulation decreased for increasing severity of COPD. In conclusion, drawing impairment correlates with depressed sympathetic modulation in patients with COPD, and both might be indexes of COPD severity.