Aim: The present randomized clinical trial was designed to investigate the effect of cryotherapy (cryo) utilizing chlorhexidine (CHX) as compared to saline (NS) on pain reduction after single visit endodontic treatment. Methodology: Selected patients were seeking emergency treatment of painful symptomatic irreversible pulpitis with symptomatic apical periodontitis for single rooted teeth. Sixty-eight male patients, 25 to 50 years old were distributed randomly in 4 groups of 17 each according to the final irrigation protocol: control (GI): NS at room temperature, control (GII): CHX at room temperature, intervention (GIII): cryo with NS (cryo/NS), , and intervention (G IV): (cryo / CHX) before final obturation in the same visit. Patients were trained and asked to report pain incidence and level after12, 24, 48, 72 hours and at 7 days as well as frequency of analgesic intake. Kruskal Wallis, followed by Dunn`s multiple comparisons test were used for comparison between the 4 groups, while Chi square test was used for qualitative data.The significance level was set at p ≤0.05. Results: G IV: cryo/CHX showed significantly highest pain reduction after 24, 48, and72 hours P= 0.0001. Frequency of analgesic need was insignificant for the two groups P=0.27. Conclusions: From the results of the present study it appeared that cryo helped in pain reduction whether used with CHX or NS. CHX used as a cryo material showed insignificant trend toward effective time dependent pain reduction as compared to NS. This might be because of its substantivity. Further study is needed to better clarifying this point.