Background: Changes in the humoral immune system of patients with orofacial squamous cell carcinoma are considered important factors in the pathophysiology, prognosis and management of the disease in these individuals[1]. Method: This is a cross sectional human study[2], undertaken to evaluate serum and salivary immunoglobulin levels in patients with histologically diagnosed orofacial squamous cell carcinoma (OSCC) attending the University College Hospital, Ibadan, Nigeria (Ethical approval number: UI/UCH/EC/09/014). Seventy subjects comprising 22 cases of untreated OSCC, 18 cases of OSCC receiving treatment and 30 healthy individuals were included. Levels of IgA, IgG and IgM in serum and saliva samples from subjects were determined using ELISA technique[3]. Results: Values are means ± SD compared by ANOVA and Dunnet’s tests. Subjects receiving treatment showed a significant reduction in the mean values of serum IgA, IgG and IgM compared with healthy controls (p= 0.03, 0.001 and 0.01 respectively). However, the mean values of serum IgA, IgG and IgM in untreated OSCC subjects were not significantly different from those of treated carcinoma subjects and healthy controls. Mean value of salivary IgG was significantly higher (p = 0.001) in untreated OSCC subjects compared with treated OSCC subjects and healthy controls. There was no significant difference in the mean values of salivary IgA and IgM among the groups. Correlation (Pearson’s correlation test) between serum and salivary immunoglobulins (IgA, IgG and IgM) showed no significant relationship. Conclusion: These findings may suggest that elevated salivary IgG probably plays a role in the pathophysiology of orofacial squamous cell carcinoma and hence, may be a reliable marker. In addition, serum IgA, IgG and IgM may be useful in the monitoring of patients undergoing treatment. Key words: saliva, serum, immunoglobulin, orofacial, squamous cell carcinoma