Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (O) has radiosensitizing properties in several tumor models including sarcomas. We studied safety and activity of O with external beam radiation therapy (EBRT) in patients with locally advanced soft-tissue sarcomas (STS). Methods: This phase I study first assessed four dose levels (DL1:25 mg, DL2:50 mg, DL3:100 mg, DL4:150 mg BID) of O administered in combination with EBRT (59.4 Gy in 33 fractions of 1.8 Gy) using a TITE-CRM design. Next, we recruited 15 additional patients in an expansion cohort to assess the tumor response or the histological response for patients with resectable disease. Tumor response was assessed by investigators according to RECIST 1.1 criteria. Results: A total of 41 patients (17 men, 24 women) were enrolled in both cohorts, of whom 19 (46.3%) underwent post-treatment surgery. We observed 1 DLT at DL1 (n = 5), 1 at DL2 (n = 7), 0 at DL3 (n = 11) and 1 at DL4 (n = 3) during the dose escalation. The recommended dose (RP2D) was 100 mg BID. Most common adverse events related to O and/or EBRT were acute dermatitis (G1/2 63.4% of patients, G3/4 34.1%), edema limbs (G1/2 36.6%), fatigue (G1/2 36.6%), nausea (G1/2 31.7%) and myositis (G1/2 29.3%). Among the 22 patients assessed for tumor response, 3 unconfirmed partial responses, 12 stable diseases, 5 progressive diseases, and 2 non-evaluable responses were recorded as best overall responses. The 6-month non-progression rate in that population was 9.1% [95%CI 1.1%-29.2%]. Six (31.6%) good histological responses and 9 (47.4%) poor responses were observed on the 19 patients who underwent surgery (4 responses non-available). Conclusions: This study shows that the combination of O with EBRT is well tolerated and lead to encouraging downstaging. A little less than half of the population was able to benefit from surgery with positive results in more than 30% of the cases and the rest of the population showed a promising stability of the disease at 6 months. We are currently awaiting a minimum of one year follow-up for the expansion cohort to assess survival. Clinical trial information: NCT02787642.