Background: The main purpose was to assess the efficacy of negative pressure wound therapy (NPWT) for surgical site infection (SSI) in elective open and laparoscopic open-assisted colorectal surgery. The primary end point was to establish SSI within 30 days post-operatively. The secondary aim was hospital stay and to assess SSI predictors in a multivariable analysis. Patients and Methods: A prospective cohort study was undertaken between January 2017 and December 2018 in patients undergoing elective colorectal surgery, both through open and minimally invasive approaches, to whom NPWT or fully occlusive dressing were applied. Baseline data were compared between the two groups and multivariable analysis was performed to identify SSI risk factors. Results: Two hundred patients were included: 100 NPWT patients and 100 closed dressing patients. No differences between the two groups were found. The incidence of SSI in the control dressing group was 19% versus 9% in the NPWT group, which was substantially different (odds ratio [OR] 0.30; 95% confidence interval [CI] 0.11-0.83; p = 0.02). No differences were found in hospital length of stay (12.33 d in NPWT group vs. 12.39 d in the control group; p = 0.82). A body mass index (BMI) of 30-35 (p = 0.04), BMI >35 (p = 0.03), and midline wound (p = 2.68) were found to be predictors of SSI in multivariable analysis. Conclusion: The prophylactic use of NPWT in laparotomy incisions for patients undergoing elective colorectal surgery (both through open and laparoscopic approach) is associated with a reduction in SSI rates.