We evaluated the effect of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor, on vasomotor responses in diabetic patients with peripheral arterial disease (PAD). The subjects were 10 type 2 diabetes patients with PAD who received 600 mg daily of naftidrofuryl, orally for 12 weeks. Another study group included 10 type 2 diabetes patients with PAD who did not receive naftidrofuryl (W); 10 healthy subjects were selected as controls (C). The patient groups were matched for age, sex and body mass index. All patients had a decreased ankle brachial index (ABI) in both legs (0.73 ± 0.17). We recorded changes in laser Doppler flux (LDF; PeriFlux 4001, Perimed). Basal LDF (b-LDF), vasoconstrictor response (v-LDF) to deep inspiration, postocclusive hyperaemia (m 1-LDF) on the pulp of the toe (in apical skin), and heat (+44°C; PeriTemp 4005)-induced hyperaemia (m 2-LDF) on the dorsum of the foot (non-apical skin) were estimated using PeriSoft software. After treatment, the following indices improved (mean ± SD): b-LDF at both locations (apical skin: 48 ± 34 vs. 78 ± 42 PU, p < 0.01; non-apical skin: 14 ± 9 vs. 27 ± 24 PU, p < 0.05), v-LDF (13.5 ± 12.4 vs. 26.7 ± 15.5%, p < 0.001), m1-LDF (100 ± 54 vs. 133 ± 60 PU, p < 0.01) and m2-LDF (61 ± 31 vs. 95 ± 49 PU, p < 0.01). Treatment also increased local skin temperature at both measured places (pulp: p < 0.001; dorsum, p < 0.01). After 12 weeks no significant changes of LDF indexes were observed in the patients without naftidrofuryl therapy (p > 0.05). In both patient groups ABI was not significantly changed after 12 weeks and there was no close correlation between ABI and LDF indexes. Our results suggest that 12 weeks of naftidrofuryl therapy improves the cutaneous vasomotor response in diabetic patients with PAD.