The RaScaL study was a six month, single-centre, controlled, prospective phase I/II study in which subjects with diabetic macular oedema (DME) and associated peripheral nonperfusion on ultrawide-field fluorescein angiography (UWFA) were randomised to: (1) study arm: ranibizumab (0.5 mg) injection plus UWFA-guided peripheral scatter laser, or (2) control arm: triamcinolone acetonide (4.0 mg) injection plus macular laser (focal / grid).The study population consisted of 22 patients (30 eyes, eight bilateral patients) ≥18 years of age with type 1 or 2 diabetes mellitus glycosylated hemoglobin (HbA 1c ) ≤12%, and visual impairment due to DME. The key inclusion criteria were: (1) stability of diabetes within three months; (2) visual impairment due to DME in at least one eye that was eligible for macular laser treatment in the opinion of the investigator, and (3) peripheral nonperfusion on UWFA of at least three clock hours. Mean initial Early Treatment Diabetic Retinopathy Study and best corrected visual acuity (ETDRS BCVA) was 54 letters (20/80) in the control and 59 letters (20/60) in the RaScaL group. Mean central foveal thickness (CFT) on optical coherence tomography (OCT) was 473 in the control group and 493 in the RaScaL group. Both the RaScaL and the control (combination intravitreal triamcinolone acetonide 4.0mg plus macular laser) groups achieved visual acuity improvements at six months, of 13 and 10 letters, respectively. None of the RaScal patients suffered a loss of visual acuity at six months. There was also improvement in the CFT on OCT in both groups with a trend for less thickening in the RaScaL group (279 vs. 367μm). The RaScaL group trended to a more gradual but consistent improvement in visual acuity and CFT; conversely, the control group of triamcinolone plus macular laser demonstrated a trend toward earlier improvement in initial visual acuity and OCT but later recurrence of DME. The RaScaL group required rescue treatment for recurrent DME in only 33% of patients at six months as compared to 80% in the control group. This difference was clinically and statistically significant (p<0.003). This finding supports the hypothesis that this subgroup of DME may have an underlying pathobiology significantly driven by peripheral retinal ischaemia, resulting in VEGF production, and ultimately leading to increased permeability of the retinal vasculature in the macula. As a result, treatment with this approach of peripheral scatter laser and VEGF inhibition may result in better durability, decreased burden of injections, and long-term control in this subset of patients with DME. Decision by imaging signatures is an attractive concept that requires further trials. This study was limited by its small size, slight imbalance in baseline visual acuity between groups and limited follow-up and imaging technology. Although Optos P200MA provides excellent, reliable, reproducible images through small pupils, however, the view of the anterior periphery and the superior and inferior views may be limited by the lids or lashes. Through six months of follow-up, this small pilot study suggests that the RaScaL treatment strategy consisting of ranibizumab plus UWFA-guided peripheral scatter laser may be a reasonable therapeutic approach in treating patients with DME associated with peripheral retinal nonperfusion.