In a hospital based case-control study, 272 subjects (136 cases and 136 normal healthy individuals) were included. Scraped exfoliated cytosmears were collected. The objective was to detect the cytological atypias and to investigate their diagnostic importance in multi-stage human oral carcinogenesis. In the present study, ten types of cytological atypias were detected from different oral sites. Based on the pattern of keratinisation and morphological peculiarities, these are named as (1) Keratinized spindle cell (KSC) (2) Keratinized tadpole cell (KTC), (3) Keratinized strap (Antischkow) cell (KSC-A), (4) Large keratinized fibre cell (LKFC), (5) Small keratinized fibre cell (SKFC), (6) Large keratinized round cell (LKRC), (7) Small keratinized round cell (SKRC), (8) Micronucleated cell (MNC), (9) Plump keratinized squamous cell (PKSC) and (10) Non-keratinized malignant squamous cell (NMSC). Except NMSC- which was observed to be non-keratinized and poorly differentiated, all other cells were keratinized and appear to be either well differentiated or moderately differentiated. Nuclear Cytoplasmic (N/C) ratios in these atypias were observed to be in increasing trend from PKCS (1:27.9 in male and 1:28.9 in female)) to NMSC (1:1 in both sexes). Diagnostic tests also indicated that the Sensitivity was 83.5%, Specificity was 100%, positive predictive value (PPV) was 100%, negative predictive value (NPV) was 30% and the accuracy was found to be 84.6%. Genesis of such diagnostic cytological atypia indicates a sign of cellular alteration and index of oral carcinogenesis. Therefore, the detected pleomorphic atypical may be considered as ideal candidates for diagnosis, grading and early detection of human oral neoplasms.