Due to frequent cardiorespiratory events (CREs) in response to the first routine immunization (rIM), current guidelines recommend readmitting and monitoring extremely preterm infants after the second rIM, though evidence on CREs in response to the second rIM is weak. In a prospective observational study, preterm infants with an increase in CREs after the first rIM were monitored for CREs before and after the second rIM. Seventy-one infants with a median gestational age of 26.4 weeks and a median weight of 820 g at birth were investigated at a median postnatal age of 94 days. All but seven infants showed an increase in CREs after the second rIM. The frequency of hypoxemias ( < 0.0001), apneas ( = 0.0003) and cardiorespiratory events requiring tactile stimulation (CRE-ts) ( = 0.0034) increased significantly. The 25 infants (35%) presenting with CRE-ts were significantly more likely to have been continuously hospitalized since birth ( = 0.001) and to receive analeptic therapy at the first rIM ( = 0.002) or some kind of respiratory support at the first ( = 0.005) and second rIM ( < 0.0001). At a postmenstruational age of 43.5 weeks, CRE-ts ceased. Our data support the recommendation to monitor infants who fulfil the above-mentioned criteria during the second rIM up to a postmenstruational age of 44 weeks.