Oral lichen planus (OLP) is a common disease of the oral mucosa with worldwide distribution and overall prevalence of 0.5–2.2%. Its etiology remains unclear, although the role of autoimmunity is supported by its association with other autoimmune diseases and the presence of auto-cytotoxic T cell clones in the lesions. Although many options for treating symptomatic OLP are available, no therapy is curative. This trial compared treatments with topical tacrolimus 0.1% ointment and topical clobetasol propionate 0.05% ointment. Forty patients with histologically proven symptomatic OLP were divided into two groups of 20 to receive clobetasol propionate (0.05%) ointment or tacrolimus (0.1%) ointment for eight weeks. Follow-up for all patients included three visits during the treatment course and one post-treatment visit. At each visit, objective improvement in the lesions was assessed by two independent investigators. The primary outcome measure was defined as the percentage of patients attaining complete response at eight weeks. Secondary outcome measures were the percentages of patients attaining complete or partial response at 8 and 12 weeks. Patient-observed improvement was evaluated at each visit. Demographic parameters and pretreatment disease characteristics were comparable between the groups. The mean net clinical score (NCS) declined progressively from baseline at each follow-up visit in both groups. In the clobetasol group, the mean NCS declined from 8.00 ± 2.65 at baseline to 2.00 ± 1.49 at 12 weeks. In the tacrolimus group, the mean NCS declined from 7.78 ± 3.25 at baseline to 1.31 ± 1.06 at 12 weeks. At each visit, the decline in mean NCS from baseline was statistically significant (< 0.05) in both groups. Complete response rates of 40% and 70%, respectively, were achieved in the clobetasol and tacrolimus groups (= 0.057). The percentages of patients reporting “good” or “very good” treatment responses at week 8 were 74% in the clobetasol group and 100% in the tacrolimus group (> 0.05). No severe adverse events were reported. Tacrolimus 0.1% ointment is an effective alternative to topical steroid and may be considered as a first-line therapy in OLP.