Associations between natural killer (NK) cell, proinflammatory cytokine stress responsivity, and cardiac autonomic responses (indexed by heart rate and heart rate variability) were assessed in 211 middle-aged men and women. Blood was drawn at baseline, immediately following color–word interference and mirror tracing tasks for the assessment of NK cell numbers, and 45 min post-stress for assessing plasma interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) responses. Heart rate variability was measured as the root mean square of successive differences (RMSSD) in R–R intervals. Increases in NK cell counts following stress were positively associated with heart rate responses independently of age, sex, socioeconomic status, smoking, and change in hematocrit. Heart rate 45 min post-stress was positively associated with plasma IL-6 post-stress, and with TNFα changes from baseline, independently of covariates. No relationship between immune responses and heart rate variability was observed. We conclude that individual differences in sympathetically-driven cardiac stress responses are associated with NK and proinflammatory cytokine responses to psychological stress.