Introduction: Oral squamous cell carcinomas (OSCCs) are malignancies which develop predominantly from preexisting potentially malignant disorders. Immunoglobulin A (IgA) in saliva and serum is responsible for local immune response. The present study evaluates the role of serum and salivary IgA in OSCC and oral potentially malignant disorders (OPMDs). Materials and Methods: Ninety individuals were recruited into the study in three groups of thirty each. The participants were categorized as control group, study Group I consisting of OPMDs, and study Group II consisting of OSCC. Serum and salivary IgA was analyzed using nephelometry. Results: Serum IgA showed statistically significant increase between controls and study Group II and between study Group I and study Group II (P < 0.05). Salivary IgA showed statistically significant difference between controls and study Group I and between controls and study Group II (P < 0.05). Conclusion: The results show increased serum IgA in OSCC group as compared to controls while salivary IgA increased in both OPMD and OSCC groups. Thus, the present study indicates a role for serum IgA in OSCC while salivary IgA has potential as a prognostic indicator in OPMDs and OSCCs.