Background: Due to long-standing concerns that heavy-load lifting could increase the risk of developing lymphedema, breast cancer survivors have been advised to refrain from resistance exercise with heavy loads. This study prospectively evaluated the effect of heavy-load resistance exercise on lymphedema development in women receiving chemotherapy for breast cancer. Material and Methods: Physically inactive women receiving adjuvant chemotherapy for breast cancer (n = 153) were randomized to a HIGH (supervised, multimodal exercise including heavy-load resistance exercise: 85–90% 1 repetition maximum [RM], three sets of 5–8 repetitions) versus LOW (pedometer and one-on-one consultations) 12-week intervention. Outcomes (baseline, 12 and 39 weeks) included lymphedema status (extracellular fluid [bioimpedance spectroscopy] and inter-arm volume % difference [dual-energy X-ray absorptiometry], lymphedema symptoms [numeric rating scale 0–10]), upper-extremity strength (1 RM), and quality of life domains (EORTC- BR23). Linear mixed models were used to evaluate equivalence between groups for lymphedema outcomes (equivalence margins for L-Dex, % difference and symptoms scale: ±5, ±3% and ±1, respectively). Superiority analysis was conducted for muscle strength and quality of life domains. Results: Postintervention equivalence between groups was found for extracellular fluid (0.4; 90% CI −2.5 to 3.2) and symptoms of heaviness (−0.2; −0.6 to 0.2), tightness (−0.1; −0.8 to 0.6) and swelling (0.2; −0.4 to 0.8). Nonequivalence was found for inter-arm volume % difference (−3.5%; −17.3 to 10.3) and pain (−0.7; −1.3 to 0), favoring HIGH. Strength gains were superior in the HIGH versus LOW group (3 kg; 1 to 5, p < .05). Further, clinically relevant reductions in breast (−11; −15 to −7) and arm (−6; −10 to −1) symptoms were found in the HIGH group. Conclusion: Findings suggest that physically inactive breast cancer survivors can benefit from supervised heavy-load resistance exercise during chemotherapy without increasing lymphedema risk. Trial registration: ISRCTN13816000