Our study describes the clinical outcome of total ankle replacement (TAR) performed in patients with moderate to severe varus deformity. Between September 2004 and September 2007, 23 ankles with a varus deformity > or = 10 degrees and 22 with neutral alignment received a TAR. Following specific algorithms according to joint congruency, the varus ankles were managed by various additional procedures simultaneously with TAR. After a mean follow-up of 27 months (12 to 47), the varus ankles improved significantly in all clinical measures (p < 0.0001 for visual analogue scale and American Orthopaedic Foot and Ankle Society score, p = 0.001 for range of movement). No significant differences were found between the varus and neutral groups regarding the clinical (p = 0.766 for visual analogue scale, p = 0.502 for American Orthopaedic Foot and Ankle Society score, p = 0.773 for range of movement) and radiological outcome (p = 0.339 for heterotopic ossification, p = 0.544 for medial cortical reaction, p = 0.128 for posterior focal osteolysis). Failure of the TAR with conversion to an arthrodesis occurred in one case in each group. The clinical outcome of TAR performed in ankles with pre-operative varus alignment > or = 10 degrees is comparable with that of neutrally aligned ankles when appropriate additional procedures to correct the deformity are carried out simultaneously with TAR.