ABSTRACT Purpose The study was conducted to compare intralesional methylprednisolone acetate 40 mg/ml (Depo-Medrol) injection with incision and curettage in the treatment of chalazia. Method A prospective, interventional clinical study was conducted. Seventy-seven patients that met the inclusion criteria and gave informed consent were randomized to receive either intralesional methylprednisolone injection or incision and curettage. Patients were followed up at two weeks and at one month, and the treatment was repeated when indicated. Results Seventy-three patients completed the study. At two weeks, after one treatment, there was a significant difference in outcome (p = 0.002) between the two groups: 10 (27%) chalazia resolved after intralesional methylprednisolone injection and 23 (64%) after incision and curettage. At one month however, there was no statistical difference (p = 0.223) in outcome between the two groups: resolution occurred in 24 patients (65%) after intralesional methylprednisolone injection, and in 28 patients (78%) after incision and curettage. In cases that were successfully treated at one month, 58% required a second treatment with intralesional injection, which was significantly more (p = 0.020) than the 18% with incision and curettage. In both groups, the initial chalazion size and duration did not significantly influence the outcome of treatment. The average time to perform intralesional injection (39 seconds) was significantly quicker (p = 0.000) than the average time for incision and curettage (2 minutes 46 seconds). In 3 out of 37 injected patients, a slight subcutaneous methylprednisolone deposit was visible at one month. Conclusion Incision and curettage remains the gold standard in the treatment of chalazia, but intralesional methylprednisolone (Depo-Medrol) injection is an useful alternative treatment modality.