The present study was conducted to assess the applicability of liquid-based cytology (LBC) using an innovative oral brush, Orcellex. Fifty healthy volunteers were recruited. From each subject, four samples were collected using “Orcellex” from apparently normal oral mucosal sites. A plastic spatula was also used to obtain an additional sample. Data on the tolerability and acceptability of the Orcellex were collected from the subjects, together with assessments of the adequacy of LBC slide preparations for cellularity, preparation quality, and the types of cells observed. The Orcellex brush was well accepted by the volunteers, who reported relatively little pain. Orcellex brush LBC preparations were of good quality in terms of cell morphology and staining, with a clean background. Only two smears (2/200; 1%) were found to be inadequate due to low cellularity. All of the plastic spatula LBC preparations were inadequate. Representative cells from all layers of the different oral epithelia examined were documented. Oral liquid-based cytology using the Orcellex brush may have considerable potential for early detection of oral cancer and precancer.