Background: Synovial sarcoma (SS) is one of the commonest non-Rhabdomyosarcoma Soft Tissue Sarcomas (STS) in Adolescent and Young Adults. It is a chemosensitive, high-grade tumor with a tendency for local and metastatic recurrence. While the frontline therapy is doxorubicin, treatment options in later lines are scarce. Gemcitabine docetaxel combination has demonstrated its role in relapsed STS and promising potential in frontline setting in recent times. The major STS types in previous trials included leiomyosarcomas and pleomorphic sarcomas but in SS, this regimen has not been explored. We conducted this study on gemcitabine and docetaxel combination in relapsed metastatic/locally advanced unresectable SS. Methods: This is a phase II, single-arm study in patients (pts) of metastatic/locally advanced unresectable SS relapsed post atleast one line of treatment aged between 15-75 years, ECOG performance status (PS) 0-2, adequate organ function and measurable disease by RECIST 1.1. Treatment was gemcitabine 900 mg/m² on days 1 and 8 plus docetaxel 75 mg/m² on day 8 with G-CSF prophylaxis for maximum 6 cycles. Adverse event (AE) profile was analyzed by CTCAE 5.0, quality of life (QoL) assessed 4-weekly by EORTC QLQ-C30 questionnaire and response assessed by RECIST at 12 weeks. Primary endpoint, 3-month Progression-free survival rate (PFR) was required to be 40%. Results: 22 pts were enrolled between 3/2020 – 9/2021 with median age 32 (range 15-60 years); 13 (59%) patients were male; ECOG PS was 1 in 13 (59%) and 2 in 9. Extremity and lung were the commonest primary and metastatic sites respectively with 20 (90.9%) pts having metastases. 50% pts received the study treatment in 2^nd line, 36.3% in 3^rd line and the remaining in 4^th line. The 3-month PFR was 45.4%, median PFS was 3 months, OS 67% at 7 months follow-up and Overall Response Rate (ORR) was 4.5% (1 PR). There was statistically significant worsening in QoL parameters of cognitive functioning, fatigue, dyspnea, appetite loss, nausea/vomiting at 12 weeks. Progression-free pts had better QoL in cognitive and emotional function, fatigue, pain and global health status. Beyond 12 weeks, 7 out of 10 non-progressors continued the treatment (1 patient each discontinued treatment due to death, change to TKI and enrolment in another trial). The most common AEs were fatigue, nausea/vomiting, mucositis, diarrhea, alopecia, anemia, transaminitis; Grade > 3 AEs (31.8%) included anemia, neutropenia, hyperbilirubinemia, transaminitis, mucositis. There was no febrile neutropenia. Conclusions: This is the first prospective study on gemcitabine docetaxel in patients of SS. The trial met its primary endpoint of 3-month PFR more than 40% which is promising in relapsed population. The improved QoL among progression-free pts is encouraging. Gemcitabine docetaxel regimen exhibits efficacy and safety to be considered for use in relapsed SS. Clinical trial information: CTRI/2020/02/023612.