Optical coherence tomography (OCT) has become the invasive imaging modality of choice for coronary stent assessment due to its unmatched spatial resolution. Neointimal calcification (NC) is a rare finding, observed in 5-10% of in-stent restenosis (ISR) neointima. The impact of NC on percutaneous coronary intervention of ISR is unknown. We therefore present the outcome of six unique cases of ISR and NC in which OCT was used to evaluate the impact of NC on the quality of stent-in-stent deployment for the treatment of ISR. This series demonstrates for the first time the impact of NC on stent expansion, a finding which might help guiding percutaneous coronary intervention for ISR with NC.