Abstract Aims Cardiac allograft vasculopathy (CAV) remains the ‘Achilles’ heel’ of successful long-term outcome after heart transplantation (HTx). Percutaneous coronary intervention (PCI) with bare-metal stents (BMS) and first (I) generation drug-eluting stents (DES) has been previously considered as a palliative treatment option in this setting, for the higher rate of restenosis and the lack of a survival benefit over medical therapy. Few data on the performance of second (II) generation DES in CAV are currently available. Our study aims to compare the efficacy and safety of PCI with I and II generation DES in patients with CAV. Methods and results All consecutive heart transplant patients who underwent urgent or elective PCI with I or II generation DES between 2003 and 2020 at Foundation IRCCS Polyclinic San Matteo (Pavia) were enrolled. The extent of revascularization for each patient was assessed calculating the post-procedural residual SYNTAX score. The primary endpoint was a composite of MACE [any myocardial infarction, cardiovascular death and target vessel revascularization (TVR)] at 3-year. The secondary endpoint was target lesion failure (TLF) at 3-year—composite of cardiovascular death, target vessel myocardial infarction (TV-MI) and target lesion revascularization (TLR). A total of 90 transplant patients (113 coronary lesions) were included: 28 patients (32 lesions) were treated with I generation DES and 62 patients (81 lesions) with II generation DES. No differences between the two study groups were identified in term of number of stents per patient implanted (overall 1.63 ± 0.87, P-value = 0.628), total stent length per patient [overall 26 (25th–75th : 18–44) mm, P-value = 0.486], pre-PCI [overall 8 (25th–75th: 5–15), P-value = 0.286], and post-PCI residual [overall 1.5 (25th–75th: 0–4), P-value = 0.187] SYNTAX score. In the whole study population, the primary and secondary endpoints occurred in 28 (33%) and 23 (27%) cases respectively, with a 3-year Kaplan–Meier estimate of freedom from MACE of 64%, and from TLF of 71%. No statistical differences between the two study arms were found (MACE log-rank test P-value = 0.269, TLF log-rank test P-value = 0.260). At multivariate Cox regression analysis, while treatment with II generation DES was confirmed to not predict the risk of MACE (HR: 0.70, CI: 0.32–1.5, P-value = 0.368), a borderline significant higher rate of events was found in patients with a post-PCI residual SYNTAX score >8 (HR: 2.37, CI: 0.98–5.73, P-value = 0.054). However, patients treated with II generation DES experienced a lower rate of TVR (3-year Kaplan-Meier estimate of freedom from TVR I generation DES 69% vs. II generation DES 85%, log-rank test P-value = 0.058, univariate Cox regression analysis HR: 0.4, CI: 0.13–1.07, P-value = 0.069). Conclusions In heart transplant patients with CAV, compared with I generation DES, PCI with II generation DES did not show to reduce the risk of MACE and TLF, guaranteeing however a lower rate of TVR. In this complex clinical scenario, incomplete revascularization (defined as a residual post-PCI SYNTAX score > 8) was associated with worse outcome at 3-year follow-up.