<b><i>Background:</i></b> The influence of the first immunization on cardiorespiratory (CR) stability in very preterm infants is still a controversial subject. <b><i>Objectives:</i></b> To describe the changes induced by immunization on heart and respiratory rate variability (HRV-RRV) and to test a potential association between preimmunization profiles and postimmunization CR events. <b><i>Methods:</i></b> Continuous 72-hour CR recordings and 2.5-hour polysomnographic recordings were performed on very preterm infants immunized after 7 weeks. The results are expressed as medians (interquartile ranges). <b><i>Results:</i></b> Immunization was performed on 31 very preterm infants [28 weeks' gestation (26.9-29), birth weight: 965 g (795-1,105)], and was associated with an increased incidence (p < 0.01) of events lasting more than 10 s: bradycardia <80 bpm [2.2 (1.1-7) vs. 1.8 (1-4)/12 h], desaturation [17.6 (9.4-36.4) vs. 13.9 (7.7-33.8)/12 h] and associated bradycardia-desaturation [I_B+D, 4.1 (1.4-7.3) vs. 2.4 (1-4.6)/12 h], with mild changes in HRV and no change in RRV. The changes in I_B+D frequency were correlated with preimmunization I_B+D frequency (r = 0.44, p < 0.05), HRV spectral parameter low frequency/high frequency ratio (LF/HF, r = 0.55, p < 0.01) and approximate entropy of HRV (r = -0.39, p < 0.05). <b><i>Conclusion:</i></b> The increase in CR events after the first immunization in very preterm infants was associated with: (1) sympathetic predominance in heart rate control (high LF/HF ratio), (2) abnormal oversimplification of HRV (low entropy) and (3) persistent respiratory rhythm control immaturity (high I_B+D before vaccine).