Lattice radiation therapy (LRT), a form of spatially fractionated radiation therapy, holds promise for treating large tumors. Despite its introduction in clinical practice around 2010, there remains limited information on its time-related outcomes despite consistently high response rates and tolerability. We assessed the time-related outcome of our palliative LRT cohort. We conducted an analysis of our LRT program, which involved 45 palliative patients with 56 lesions larger than 7 cm, treated between January 2022 and November 2023. Prospectively defined treatment protocols included delivering 20 to 25 Gy/5 fractions to the tumor with a stereotactic simultaneously integrated boost (SIB) of 60 to 65 Gy to lattice vertices (n = 45/56) or, mainly in preirradiated lesions, single fraction stereotaxy with 1 × 15 to 20 Gy to vertices only (n = 11/56). Follow-up (FU) intervals were determined based on clinical considerations, considering the mostly highly palliative situation of included patients. Outcome assessments focused on subjective benefit and objective radiologic FU response. The mean/median FU was 5.5/4.0 months (0.3-21 months). A total of 25/45 (56%) patients died after a mean/median of 3.9/2.0 months (0.3-14 months). Fourteen of 56 lesions (25%) were previously irradiated, with a mean/median of 18/13 months (4-72 months) prior to LRT. The mean/median gross tumor volume (GTV) measured 797/415 cc (54-4027 cc) and 14/13 cm (7-28 cm). Subjective statements at LRT completion were available from 37 symptomatic patients: 32/37 (87%) reported fast symptom relief, and 5/37 felt no change under LRT or at LRT completion. Early tolerance was excellent (G0-1). FU imaging was available from 40/56 lesions (71%): progression in 3/40 at first exam one at 1.5 and 4 months post-LRT, and stable disease (±10%) in 5/40 assessed at 2, 3, 3, and 4 months post-LRT. First measure shrinkage of 48%/30% (10%-100%) was found in 32/40 lesions (80%) after a mean/median of 2.8/3 months (0.3-7 months). Maximum shrinkage over time based on 21 cases with at least 1 FU imaging measured a mean/median of 62%/60% after 6.2/5.5 months. The duration of radiologic response was a mean/median of 7.4/7.0 months (1-21 months). Short-course LRT emerged as an effective and well-tolerated palliative option for very large lesions, whether treatment-naïve or previously irradiated. Nearly 90% of symptomatic patients reported significant subjective benefit, and 80% of assessed lesions demonstrated tumor shrinkage ≥10%, with a mean response duration of >6 months.