AIM: To assess the impact of two root canal treatment protocols on the oral health-related quality of life (OHRQoL) of patients in need of root canal treatment on their anterior teeth. METHODOLOGY: The sample consisted of 120 participants (mean age: 34 years) enrolled in a pragmatic randomized clinical trial evaluating two root canal treatment protocols. Anterior teeth with nonvital pulps were allocated for root canal preparation with either hand files and filled with lateral compaction of gutta-percha (manual protocol) or canal preparation with a single file in a reciprocating movement and filled with a single cone technique (Reciproc protocol). OHRQoL data were assessed using the Oral Health Impact Profile instrument (OHIP-14), which was administered before the root canal intervention (baseline), and 6 and 12 months after treatment. Demographic and clinical characteristics of participants were collected at baseline. Data were analysed using bivariate analyses, Poisson univariate and multiple regression (α = 0.05). RESULTS: The drop-out rate from baseline was 27% and 28% at 6 and 12 months after treatment, respectively. Both root canal protocols significantly enhanced patients' OHRQoL, regardless of the follow-up time (P < 0.001). After 6 months, patients treated with the Reciproc protocol had significantly lower OHIP-14 overall scores (P = 0.030), as well as significantly lower scores for psychological discomfort (P = 0.031) and social disability (P = 0.013). After 12 months, no significant difference was observed between the two root canal protocols for OHIP-14 overall scores (P = 0.174). Either large or moderate effect sizes were observed for all domains and overall scores at both evaluation times, irrespective of the protocol. Low-income persons (RR = 2.03) and the Reciproc protocol (RR = 1.52) had a higher likelihood of a positive impact on OHRQoL 12 months after root canal treatment. CONCLUSIONS: The two root canal protocols improved the OHRQoL and differences in scores were observed only after 6 months with poorer OHRQoL for the manual protocol. After 12 months, patients with low-income status and treated with Reciproc were associated with a greater improvement in OHRQoL scores.