Objective To investigate the role of anti-herpes ximplex virus (HSV)-1 IgM secreting cells detection assay in early diagnosis of herpes simplex encephalitis. Methods Twenty-three herpes simplex encephalitis cases and 40 control cases were included in this study. Anti-HSV-1 IgM secreting cells and anti-HSV-1 IgM were retrospectively tested in the patients' cerebrospinal fluid by enzyme-linked immunosorbent spot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA), respectively. The data analysis was performed by using Fisher Exact Test. Results Using ELISPOT method for detection of 9 HSV-1 encephalitis patients' and 16 clinical control cases anti-HSV-1 IgM secreting cells within two weeks after disease onset, the sensitivity of ELISPOT for detecting anti HSV-1 IgM secreting cells in the cerebrospinal fluid was 88.9% (8/9) and the specificity was 93.8%(15/16). On the other hand, the sensitivity of ELISA for detecting anti-HSV-1 IgM in ccrebrospinal fluid was 16.6% (2/12) and the specificity was 88.2% (15/17) when using ELISA method for detection of 12 HSV-1 encephalitis patients' and 17 clinical control cases's anti-HSV-1 IgM secreting cells. The sensitivities of the two methods were statistically different (P<0.01). Conclusion Compared to ELISA, ELISPOT for detecting the anti-HSV-1 IgM secreting cells in cerehrospinal fluid is a more sensitive method for early diagnosing herpes simplex encephalitis.