S-100 immunohistochemical staining may detect nerve involvement in early stages of tuberculoid spectrum of leprosy. This study investigated the use of S-100 in early diagnosis of the tuberculoid and borderline tuberculoid leprosy and compared its sensitivity with hematoxylin and eosin (HE) stains in discerning the nerve involvement. To study the different histopathological patterns of nerve involvement in tuberculoid and borderline tuberculoid leprosy on S-100 immunostaining and also to compare the sensitivity of HE stain with S-100 immunostain in discerning the nerve involvement in these cases. This was a descriptive, prospective and retrospective analytical study, which included patients with tuberculoid spectrum of leprosy. Histopathological examination (HPE) and immunohistochemical (IHC) analysis were performed on all skin biopsies using HE stain and S-100 immunostain, respectively. Then the sensitivities of both the stains in discerning the nerve involvement were calculated and the data was analyzed using SPSS software version 22 by applying chi-square test. The study included a total of 58 patients [tuberculoid (n=28), borderline tuberculoid (n=30)]. The mean age was 43 yrs. The most common clinical manifestation was hypopigmented patches (n=40, 70%) with loss of sensation (n=39, 68.3%). HPE revealed 36 cases with well-defined granulomas, 22 cases with ill-defined granulomas and 41 cases with nerve destruction. IHC analysis showed four different patterns of nerve damage (fragmented, n=32; infiltrated and fragmented, n=14; infiltrated, n=10; intact, infiltrated and fragmented; n=1). The sensitivity and positive predictive value (PPV) of HE staining in delineating the nerve involvement were 68.96% and 100%, respectively. Whereas, the sensitivity and PPV of S-100 IHC were 100% each. Less number of cases. Use of S-100 IHC along with HPE aids in early, accurate and confirmatory diagnosis.