BACKGROUND: Erythema multiforme (EM) is an acute mucocutaneous syndrome characterized by typical and/or atypical target lesions on the skin. The etiology is still not clear, but EM may be related to infection or medication. Clinically, there are cases of EM with atypical target lesions with generalized distribution without, or with minimal, mucosal lesions. The causes remain unknown. However, T helper cells 1 (Th1) may play an important role in EM. AIMS: The aim of the study was to investigate serum concentrations of some Th1-derived cytokines in generalized EM or generalized EM -like eruptions. METHODS: This was a sectional and descriptive study conducted at the National Hospital of Dermatology and Venereology, in Hanoi, Vietnam, from April 2017 to August 2019. There were 33 EM patients, and 32 healthy controls (HCs) participated. Serum interleukin (IL)-2, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) levels were measured using the fluorescence covalent microbead immunosorbent assay (ProcartaPlex Immunoassay Panels kit, Thermo Fisher Scientific, USA). The Mann–Whitney U-test was used to compare the serum IL levels of the two groups. Differences were considered to be statistically significant at p < 0.05. RESULTS: The mean age of the EM patients was 42.2 ± 17.5 years, ranging from 19 to 76 years old. Men accounted for 30.3%, women accounted for 69.7%. There were 22 patients with <1 week of onset, accounting for 66.7%; 11 patients with 1 week and those with more than 1 week accounted for 33.3%. There were 60.6% of patients using drugs before the onset. Most patients had pruritus (97%), and all had diffusely distributed skin lesions. Only 15.2% of the patients had mucosal lesions. There are 30.3% of patients with fever. The serum IFN-γ concentration of the EM group was 5.35 ± 9.88 pg/mL, higher than that of the HCs group (0.35 ± 0.77 pg/mL), the difference was statistically significant with p = 0.01 (Mann–Whitney U). The concentrations of IL-2 and TNF-α of the HCs were 24.32 ± 27.94 pg/mL and 109.74 ± 126.73 pg/mL, respectively, higher than those of the EM group (3.37 ± 5.94 pg/mL and 5.86 ± 11.88 pg/mL, respectively). The difference was statistically significant with p < 0.001. Age did not correlate with serum concentrations of cytokines in the EM group. CONCLUSION: In generalized EM, serum concentrations of IFN-γ are statistically significantly higher than those of HCs but serum concentrations of IL-2 and TNF-α were lower. There is no correlation between age and serum concentrations of cytokines in generalized erythema multiform.