Acute ischaemia is mostly caused by the rupture of an unstable atherosclerotic plaque in a coronary artery, resulting in platelet accumulation and thrombus formation, which closes the lumen of the coronary vessel. Many different factors can cause atherosclerotic plaques to occlude the lumen of a coronary artery, including factors that increase vascular inflammation and blood platelet aggregation, as well as genetic factors. L-selectin is an adhesion molecule encoded by the human SELL gene, playing an important role in leukocyte adhesion to the endothelium and the development of inflammation. Guanylate cyclase 1 soluble subunit alpha 1 (GUCY1A1) is a gene that affects vasoreactivity and platelet function, thereby influencing thrombotic processes and the risk of developing thrombotic lesions in the coronary vessels. In SELL and GUCY1A1 genes, several polymorphisms have been detected, which may affect gene expression. The aim of our study was to assess the association between the SELL rs2205849 and rs2229569 and GUCY1A1 rs7692387 polymorphisms with the risk of acute coronary syndromes in the form of unstable angina pectoris, and the association between these polymorphisms and selected clinical parameters affecting the risk of developing ischemic heart disease. The study included 232 patients with unstable angina. The diagnosis of unstable angina was achieved by a typical clinical presentation and confirmation of significant coronary artery lumen stenosis (>70%) during coronary angiography. There were no statistically significant differences in GUCY1A1 rs7692387 and SELL rs2205849 and rs2229569 polymorphism distribution between the total study and the control groups. However, when only analysing patients over 55 years of age, we found a decreased frequency of the GUCY1A1 rs7692387AA genotype (AA vs. GA + GG, OR: 0.07; 95% CI: 0.01−0.78) and an increased frequency of the SELL rs2205849 CC genotype (CC vs. TC + TT p = 0.022) and SELL rs2229569 AA genotype (AA vs. GA + GG p = 0.022) in patients with unstable angina. Our results suggest that the SELL rs2205849 and rs2229569 and GUCY1A1 rs7692387 polymorphisms are not risk factors for unstable angina in the Polish population. The GUCY1A1 rs7692387 polymorphism may increase the risk of unstable angina in patients younger than 55 years, while the SELL polymorphisms rs2205849 and rs2229569 may increase the risk of unstable angina in patients older than 55 years in the Polish population.