Objective Our objective was to compare off-pump coronary artery bypass surgery carried out via a left anterolateral thoracotomy (ThoraCAB) or via a conventional median sternotomy (OPCAB). Background Recent advances in minimally invasive cardiac surgery have extended the technique to allow complete surgical revascularization on the beating heart via thoracotomy. Methods Patients undergoing nonemergency primary surgery were enrolled between February 2007 and September 2009 at 2 centers. The primary outcome was the time from surgery to fitness for hospital discharge as defined by objective criteria. Results A total of 93 patients were randomized to off-pump coronary artery bypass surgery via a median sternotomy (OPCAB) and 91 to off-pump coronary artery bypass surgery via a left anterolateral thoracotomy (ThoraCAB). The surgery was longer for patients in the ThoraCAB group (median, 4.1 vs 3.3 hours) and there were fewer with more than 3 grafts (2% vs 17%). The median time from surgery to fitness for discharge was 6 days (interquartile range, 4-7) in the ThoraCAB group versus 5 days (interquartile range, 4-7) in the OPCAB group ( P  = .53). The intubation time was shorter, by on average 65 minutes, in the ThoraCAB group ( P  = .017), although the time in intensive care was similar ( P  = .91). Pain scores were similar ( P  = .97), but more analgesia was required in the ThoraCAB group (median duration, 38.8 vs 35.5 hours, P  < .001; tramadol use, 66% vs 49%, P  = .024). ThoraCAB was associated with significantly worse lung function at discharge (average difference, −0.25 L, P  = .01) but quality of life scores at 3 and 12 months were similar ( P  = .52). The average total cost was 10% higher with ThoraCAB ( P  = .007). Conclusions ThoraCAB resulted in no overall clinical benefit relative to OPCAB.