Introduction: Recent retrospective studies suggest potential large patient s benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. Methods: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. Results: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0u20131 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2u20133 patients, HR=0.50 [0.25u20130.97], p = 0.042). Morning PS0u20131 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1u20133 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48u201314:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). Conclusions: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0u20131 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.