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(1) Background. One of the causes of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is thrombus formation in situ followed by lysis, resulting in a morphologically normal angiogram but with an underlying prothrombotic state that is potentially predisposed to recurrence. Recent studies have shown that a subset of MINOCA patients may have thrombophilic conditions at screening. Objective: To compare the prothrombotic trend in MINOCA patients with that of subjects with MI and obstructive coronary arteries (MIOCA) by testing for known congenital thrombophilias and markers of coagulation activation. (2) Materials and methods. Screening included congenital thrombophilias (factor V Leiden; assessment of protein C, protein S, and antithrombin III) and eight genes. Of these, four genes represented the folate pathway enzymes: MTHFR 677 C>T (rs1801133), MTHFR 1298 A>C (rs1801131), MTR 2756 A>G (rs1805087), and MTRR 66 A>G (rs1801394). The other four genes represented the blood coagulation system: F13 (163 G>T) rs5985, F1 (−455 G>A) rs1800790, GP IIb–IIIa (1565 T>C) rs5918, and PAI-I (−675 5G>4G) rs1799889. Additionally, we examined the levels of homocysteine and lipoprotein (LP) (a). (3) Results. Our study included 269 patients: 114 MINOCA patients and 155 MIOCA patients with lesions of one coronary artery. The frequencies of polymorphisms in the genes of the blood coagulation system and the folate pathway did not differ between the groups. The following genes were associated with in-hospital mortality in the MINOCA group: MTHFR 1298 A>C rs1801131 (OR 8.5; 95% CI 1.67–43.1) and F1 (−455 G>A) rs1800790 (OR 5.8; 95% CI 1.1–27.8). In the MIOCA group, the following genes were associated with in-hospital mortality: MTHFR 1298 A>C rs1801131 (OR 9.1; 95% CI 2.8–28.9), F1 (−455 G>A) rs1800790 (OR 11.4; 95% CI 3.6–35.9), GP IIb–IIIa (1565 T>C) rs5918 (OR 10.5; 95% CI 3.5–30.8), and PAI-I (−675 5G>4G) rs1799889 (OR 12.9; 95% CI 4.2–39.7). We evaluated long-term outcomes (case fatality rate, recurrent MI, and stroke) over a period of 12 months in both groups. The variables associated with these outcomes were laboratory parameters, such as protein C deficiency, hyperhomocysteinemia, and a content of LP (a) > 30 mg/dL. However, we did not reveal the prognostic value of polymorphisms of the studied genes representing the blood coagulation system and the folate pathway. (4) Conclusion. We established no statistically significant differences between the MINOCA and MIOCA groups in the prevalence of congenital thrombophilias and the prevalence of folate pathway enzyme genes and blood coagulation system genes. The MTHFR 1298 A>C (rs1801131) and F1 (−455 G>A) rs1800790 genes were associated with in-hospital mortality in both groups. More significant prognostic factors in both groups during the one-year period were protein C deficiency, hyperhomocysteinemia, and LP (a) > 30 mg/dL. Full article