The present study evaluated the relationship between acute chest syndrome (ACS) and autonomic nervous system (ANS) activity in patients with hemoglobin SS disease (Hb SS). Nine patients had suffered ACS were matched by age and gender to patients who had not suffered ACS and ANS activity, pulmonary function and history of painful crisis were compared. Correlations between number of episodes of ACS suffered and these variables were determined. The results demonstrated that 1) patients with a history of ACS ever had lower parasympathetic nervous system (PNS) activity and lower global ANS activity than patients with no ACS ever (p < 0.05), 2) the number of ACS episodes ever negatively correlated (p < 0.05) with PNS activity and global ANS activity and 3) There were no significant associations between lung function or a history of painful crisis in these patients. In conclusion, a history of ACS was associated with ANS dysfunction in adults with Hb SS disease.