Smaller incisions may be the major reason for reduced invasiveness of laparotomy. The aim of this study was to clarify the feasibility and safety of a minimal skin incision for colorectal cancer resection. Between April 2005 and February 2008, 122 consecutive patients (56 women, 66 men) were enrolled in this prospective study and scheduled to undergo resection for colorectal cancer using a single minimal skin incision. All of the operations were performed by a single surgeon. The patients were grouped into “small-incision” (≤7 cm), “medium-incision” (>7 and ≤14 cm), and “large-incision” (>14 cm) for comparison. The small-incision, medium-incision, and large-incision groups included 64 (52.5%), 38 (31.1%) and 20 (16.4%) patients, respectively. The median length of laparotomy incision in the small-incision and medium-incision groups (102 patients) was 7 (interquartile range 7-10) cm. There was no operative mortality. The group with larger length of skin incision had longer operation time, greater operative blood loss, higher rate of postoperative complications and longer postoperative stay. Failure of the small-incision was significantly associated with tumor location (splenic flexure/rectum) and tumor characteristics (adhesion/invasion of tumor into adjacent organs, and/or tumor diameter ≥6.0 cm). This experience suggests that the majority of colorectal cancer resection can be safely accomplished via a median length of skin incision of 7 (interquartile range 7-10) cm.