Background Intradermal administration of analgesic drugs with mesotherapy is effective for the local treatment of musculoskeletal pain. Few studies analyzed the effects of different drugs administrated with this technique. Aim The aim of this study was to compare the efficacy of diclofenac versus lysine acetylsalicylate-based mesotherapy in relieving pain (primary outcome), and disability (secondary outcome) in patients with nonspecific chronic low back pain. Design Retrospective observational study. Setting Outpatient rehabilitation medicine center. Population Records of 101 patients with nonspecific chronic low back pain. Methods Data were extracted from the outpatients records of patients affected by nonspecific chronic low back pain since 12 weeks before, treated with 5 sessions of mesotherapy with diclofenac mixtures (group A) or aspirin-lysine acetylsalicylate mixture (group B). Assessments recorded were taken before the first treatment (T0), at the end of the 5-week treatment (T1), and at 4 (T2) and 12 weeks (T3) of follow-up after the last treatment, using a pain visual analogue scale (VAS) primary outcome, Oswestry Disability Index (ODI) secondary outcome, and the Short-Form McGill Pain Questionnaire (SF-MPQ) Comparisons within and between groups were performed using the t-test, the χ2 test, and analysis of variance (ANOVA) models, as appropriate. Results Records from 101 patients consecutively were analyzed, 51 in group A (mean age and standard deviation [SD]=62.8±10.7; F/M=33/18) and 50 in group B (mean age±SD=64.1±15.8; F/M=30/20). At baseline VAS, SF-MPQ, ODI scores were respectively 7.6±1.3, 22.49±9.96, 44.80±15.55 (mean and SD) in group A; VAS, SF-MPQ, ODI scores were respectively 6.7±1.6, 18.66±9.65, 39.04±16.06 (mean and SD) in group B. Mean differences between group A and group B in the changes of scores from baseline (T0) to end of study (T3) were -1.3 (VAS), -5.81 (SF-MPQ) and -17.05 (ODI). Mesotherapy induced significant reductions in pain severity and disability in both groups with better results in diclofenac-based treatment. Conclusions This retrospective pilot study suggests the efficacy and safety of diclofenac mesotherapy for relieving pain and disability in patients affected by chronic nonspecific low back pain in a convenient sample but further studies will confirm these results. Clinical rehabilitation impact Diclofenac mesotherapy appears to be a viable treatment. to reduce pain and improve function in patients affected by chronic moderate-to-severe nonspecific low back pain.