This study aimed at assessing the proliferation rate of exfoliated cells from normal-appearing oral mucosa of crack cocaine users and alcoholics. Oral mucosal smears were collected from the tongue and floor of the mouth of 87 individuals: 26 crack cocaine users, 26 alcoholics and 35 controls. Histological slides were silver-stained using argyrophilic proteins of active nucleolar organizer regions (AgNORs) to assess the cell proliferation rate. Mean number of AgNORs per nucleus (mAgNOR) and the percentage of cells with more than 1, 2, 3 and 4 AgNORs per nucleus were calculated. Alcoholics showed higher mAgNORs (p < 0.05) in the tongue mucosa when compared to controls and crack cocaine users (3.34 ± 0.51 vs. 2.81 ± 0.77 and 2.87 ± 0.51, respectively). mAgNORs also increased (p < 0.05) in cells collected from the floor of the mouth of alcoholics when compared to controls and crack cocaine users (3.55 ± 0.57 vs. 3.18 ± 0.53 and 3.28 ± 0.39, respectively). Crack cocaine users did not show any significant differences in relation to the other two groups. Alcoholics show changes in epithelial cell proliferation in the oral mucosa even when lesions are not clinically visible. Conversely, crack cocaine use does not seem to affect cell proliferation in the oral mucosa.