The use of compression garments during exercise is recommended for women with breast cancer-related lymphedema, but the evidence behind this clinical recommendation is unclear. The aim of this randomized, cross-over trial was to compare the acute effects of wearing versus not wearing compression during a single bout of moderate-load resistance exercise on lymphedema status and its associated symptoms in women with breast cancer-related lymphedema (BCRL). Twenty-five women with clinically diagnosed, stable unilateral breast cancer-related lymphedema completed two resistance exercise sessions, one with compression and one without, in a randomized order separated by a minimum 6 day wash-out period. The resistance exercise session consisted of six upper-body exercises, with each exercise performed for three sets at a moderate-load (10-12 repetition maximum). Primary outcome was lymphedema, assessed using bioimpedance spectroscopy (L-Dex score). Secondary outcomes were lymphedema as assessed by arm circumferences (percent inter-limb difference and sum-of-circumferences), and symptom severity for pain, heaviness and tightness, measured using visual analogue scales. Measurements were taken pre-, immediately post- and 24 hours post-exercise. There was no difference in lymphedema status (i.e., L-Dex scores) pre- and post-exercise sessions or between the compression and non-compression condition [Mean (SD) for compression pre-, immediately post- and 24 hours post-exercise: 17.7 (21.5), 12.7 (16.2) and 14.1 (16.7), respectively; no compression: 15.3 (18.3), 15.3 (17.8), and 13.4 (16.1), respectively]. Circumference values and symptom severity were stable across time and treatment condition. An acute bout of moderate-load, upper-body resistance exercise performed in the absence of compression does not exacerbate lymphedema in women with BCRL.