Objective: The measurement of oral health related QoL (OHRQoL) is generally limited to dental diseases. Our objective was to evaluate patients with oral mucosal diseases using an oral health-specific questionnaire (OHIP-14), a generic health status questionnaire (SF-12) and a general psychological health questionnaire (GHQ-12) to identify the possible presence of conditions such as depression or anxiety. Methods: Consecutive patients coming to the oral health care unit of IDI-IRCCS in Rome were asked to complete the OHIP-14, the SF-12, and the GHQ-12 questionnaires. Both physicians and patients gave a global assessment of severity of disease (PhGA and PtGA, respectively) on a 5-point scale. Agreement between physiscians and patients was assessed using Cohen's K statistic. Results: Of 218 patients contacted, 206 participated in the study. Oral ulcerations were the condition with the highest impact on OHRQoL. Women had poorer OHRQoL and higher GHQ-12 scores than males. There was a very strong correlation between questionnaires scores and PtGA, but none or very scarce between questionnaire scores and PhGA. The overall K between PtGA and PhGA was 0.14, i.e., only slight, and for some conditions it was even negative (e.g., -0.23 for non-malignant lesions). Patients whose condition was “underestimated” by the physicians (i.e., PtGA>PhGA) had the worst OHRQoL and psychological status among all patients in the study. Conclusion: The administration of specific and generic questionnaires provides a complete and clinically useful picture of the impact of oral diseases on quality of life and on psychological well-being. The combined use of PhGA and PtGA allows to define a group of patients with particularly high levels of quality of life impairment and psychological distress. This may be relevant since these patient characteristics have been linked to dissatisfaction with care, poorer treatment adherence, and possibly higher probability of legal litigation.