The wound microbiome may play an important role in the wound healing process. We conducted the first systematic prognosis review investigating whether aspects of the wound microbiome are independent prognostic factors for the healing of complex wounds. We searched Medline, Embase, CINAHL and the Cochrane Library to February 2019. We included longitudinal studies which assessed the independent association of aspects of wound microbiome with healing of complex wounds while controlling for confounding factors. Two reviewers extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. We synthesised studies narratively due to the clinical and methodological heterogeneity of included studies and sparse data. We identified 28 cohorts from 21 studies with a total of 38,604 participants, including people with diabetes and foot ulcers, open surgical wounds, venous leg ulcers and pressure ulcers. Risk of bias varied from low (2 cohorts) to high (17 cohorts); the great majority of participants were in cohorts at high risk of bias. Most evidence related to the association of baseline clinical wound infection with healing. Clinical infection at baseline may be associated with less likelihood of wound healing in foot ulcers in diabetes (HR from cohort with moderate risk of bias 0.53, 95% CI 0.33 to 0.83) or slower healing in open surgical wounds (HR 0.65, 95% CI 0.51 to 0.83); evidence in other wounds is more limited. Most other associations assessed showed no clear relationship with wound healing; evidence was limited and often sparse; and we documented gaps in the evidence. There is low certainty evidence that a diagnosis of wound infection may be prognostic of poorer healing in foot ulcers in diabetes, and some moderate certainty evidence for this in open surgical wounds. Low certainty evidence means that more research could change these findings.