Cervical spondylosis (CS)-related neck pain is difficult to treat due to its degenerative nature. The aim of this nine-center, single-blinded, randomized controlled trial was to evaluate the efficacy of optimized acupuncture for CS-related neck pain. Participants who met the inclusion criteria were randomized to optimized, shallow, and sham acupuncture groups (1:1:1). The primary outcome was the change from baseline in the Northwick Park Neck Pain Questionnaire (NPQ) score at week 4. Participants were followed up until week 16. Of the 896 randomized participants, 857 received ≥1 intervention session; 280, 286, and 291 received optimized, shallow, and sham acupuncture, respectively. A total of 835 (93.2%) participants completed the study. At week 4, significant differences (P<0.001) were observed in the changes in NPQ scores between the optimized acupuncture group and both the shallow (7.72 [95% confidence interval {CI}, 5.57-9.86]) and sham acupuncture groups (10.38 [95%CI, 8.25-12.52]). The difference in the scores at week 16 between the optimized acupuncture group and the shallow (8.84 [95%CI, 6.34-11.34]) and sham acupuncture (10.81 [95%CI, 8.32-13.30]) groups were significant. The center effect indicated wide variability in the treatment effects (Cohen's d=0.01-2.19). Most SF-36 scores were higher in the optimized acupuncture group than in the other groups. These results suggest that 4-week optimized acupuncture treatment alleviates CS-related neck pain and improves the quality of life, with the effects persisting for minimum 3 months. Therefore, acupuncture can have positive effects on CS-related neck pain, although the effect size may vary widely.