Abstract Background Percutaneous coronary intervention (PCI) appears a reasonable alternative to coronary artery bypass graft in selected groups of patients with unprotected left main coronary artery (ULMCA) disease. Despite technological progression, improved operator skills and introduction of drug-eluting stents (DES), in-stent restenosis still remains a major limitation after PCI of ULMCA disease. The prognostic relevance of target lesion revascularization (TLR) after PCI of ULMCA disease is unknown. Objectives This study sought to evaluate the impact of elective, uncomplicated target lesion revascularization on long-term cardiac mortality after PCI of ULMCA disease. Methods Consecutive patients undergoing PCI for ULMCA disease between January 2003 and December 2015 in one interventional center in Italy were included. Patients presenting with cardiogenic shock, ST-segment elevation myocardial infarction (MI), as well as those undergoing urgent or complicated TLR were excluded. The primary endpoint of the study was cardiac mortality. The secondary endpoints of the study were all-cause death, MI, stroke as individual endpoints, or the composite of cardiac death, MI or stroke defined as major adverse cardiac events (MACE). Results Among the 418 patients fulfilling the study criteria, 79 (18.46%) underwent elective, uncomplicated TLR. After a median follow-up of 5.5 years, there were 23 cardiac deaths among patients undergoing elective, uncomplicated TLR versus 50 in patients not undergoing TLR. After adjusting for possible confounders, TLR was an independent predictor of cardiac mortality (Hazard ratio [HR] = 1.92, 95% confidence interval [CI]: 1.05 to 3.49; p = 0.03). Patients undergoing TLR had also significantly higher rates of the composite of cardiac death, MI and stroke compared with the no TLR group (adjusted HR = 1.76, 95% CI 1.14 to 2.72). Conclusion Elective, uncomplicated TLR after PCI of ULMCA disease is associated with increased risk of long-term cardiac mortality. Reducing the risk of TLR after PCI of ULMCA disease may potentially improve the survival of these patients.