PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect in patients treated with gemcitabine (GEM) and nanoparticle albumin-bound paclitaxel (nab-PTX) for pancreatic cancer, negatively impacting their quality of life. This study aimed to identify risk factors for significant CIPN development in a real-world setting of GEM + nab-PTX treatment to inform effective management strategies. METHODS: Patients with unresectable pancreatic cancer who received GEM + nab-PTX (n = 140) were retrospectively assessed. The primary endpoint was to identify the risk factor(s) associated with the development of problematic grade ≥ 2 CIPN within six months of treatment initiation. We also evaluated factors associated with all-grade CIPN and compared CIPN incidence across specific patient groups. RESULTS: The incidence of grade ≥ 2 CIPN was 35.0%, with 63.6% of patients experiencing symptoms of any grade. Multivariate Cox proportional hazard regression analysis identified baseline preexisting neuropathy as an independent risk factor for developing grade ≥ 2 CIPN (adjusted hazard ratio 4.03, 95% confidence interval 1.82-8.96, P = 0.0006). Conversely, dose modification of nab-PTX at or within 4 weeks of treatment initiation emerged as a protective factor (0.45, 0.22-0.91, P = 0.03). Additionally, the cumulative incidence of grade ≥ 2 CIPN was significantly lower and delayed in patients who underwent dose modification within 4 weeks compared to those who did not in the population with preexisting neuropathy (P = 0.01). CONCLUSION: Baseline preexisting neuropathy significantly increases the risk, while early dose modification of nab-PTX serves as a protective factor against developing grade ≥ 2 CIPN in patients receiving GEM + nab-PTX treatment for pancreatic cancer.