Chronic wounds have a high prevalence and wound care, treatment, and prevention consume large quantities of resources. Chronic wounds are a growing challenge for clinicians. A prospective randomized pilot study was conducted to assess the effectiveness in terms of reduction in area and safety of the combined use of negative-pressure wound therapy and nanocrystalline silver dressings as compared to negative pressure wound therapy (NPWT) alone in the management of outpatients with chronic wounds. A total of 17 patients were included in the study, 10 were treated with the combined method and 7 with NPWT. Patients were followed for 6 weeks, with a final assessment at 3 months. Clinical improvement, microbiologic data, and toxicity of silver were evaluated. The antibacterial effects of ionic silver together with the development of granulation tissue promoted by NPWT reduced significantly the median extension of the wound between weeks 3 and 6 of treatment. The combination with silver also reduced bacterial colonization with Pseudomonas aeruginosa and the bacterial load on the surface of the wound. The silver levels correlated positively with the extension of the wound, although in none of the patients’ toxic levels were reached. The combination of NPWT with nanocrystalline silver dressings was safe and as effective as NPWT alone.