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Background: To evaluate the effectiveness of hyaluronic acid (HA) gel injection with and without plasma rich in growth factors (PRGF) for the management of interdental papillary loss. Methods: A single blinded randomized clinical trial was carried out on 21 subjects with 34 sites. Patients within the age group 18–45 years who had Class I and II papillary recession in the maxillary anterior region were selected. The sites involved were randomly assigned to Group HA alone and Group HA + PRGF. The patients were recalled 4 weeks after receiving supragingival and subgingival instrumentation. HA or HA + PRGF was injected into the defective papilla at baseline and at 3 and 6 weeks. Image based measurements of Papillary Width (PW), Papillary Deficient Height (PDH), Deficient Area (DA), Deficient Volume (DV) were registered at baseline, 3 weeks, 6 weeks and 12 weeks. A vernier caliper was used to measure the papillary depth in the impression made using additional silicone impression material pre- and post-intervention. Results: There was a significant improvement in the within-group comparison of PW, PDH, DA and DV in both the groups. Group HA + PRGF showed significantly greater improvement in comparison to Group HA alone in terms of PDH, DA and DV at 6 and 12 weeks. Conclusions: Even though HA gel has already been established as a promising injectable agent in the minimally invasive treatment of interdental papillary deficiency, PRGF may also have a significant adjuvant effect when used along with HA. Further clinical studies with longer follow up duration, larger sample size and standardization of the tooth shape are required for a better understanding of the adjuvant effect of PRGF when used along with HA.