Objective. To compare the merits and demerits of PEG-IFNα-2a and PEG-IFNα-2b for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Methods. Clinical files from eighty-four CHB patients admitted to the Second Hospital of Shanxi Medical University between January 2018 and January 2019 were retrospectively analyzed and assigned to two groups: group 2a treated with PEG-IFNα-2a and group 2b treated with PEG-IFNα-2b. The clinical efficacy was compared between the above two arms, and the liver function (ALT, AST, HA, LN, and IV-C), HBV-DNA, HBsAg, HBeAg, and inflammatory factors (IFs, IL-1β, IL-6, IL-8, and TNF-α) were tested at 12 weeks (T1), 24 weeks (T2), and 48 weeks (T3). The alterations of hemodynamics (SBP, DBP, MAP, and CVP), cardiac function (LVEF and BNP), and the incidence of adverse reactions (ARs) during treatment were recorded. Finally, the patients were followed up for 2 years to investigate the quality of life (QOL) as well as the positive seroconversion rate of HBsAg and HBeAg. Results. The overall response rate was similar in the two arms (
P
>
0.05
). After treatment, the liver function, HBV-DNA, HBsAg, HBeAg, IFs, hemodynamics, and cardiac function were enormously improved (
P
<
0.05
), with faster improvement in group 2b compared with group 2a (
P
<
0.05
). The investigation of ARs identified notably lower incidence rates of alopecia, thrombocytopenia, and granulocytopenia in group 2a as compared to group 2b (
P
<
0.05
). The prognostic follow-up results revealed no distinct difference in the QOL score and the positive seroconversion rate of HBsAg and HBeAg (
P
>
0.05
); however, the quantitative results of HBV-DNA, HBsAg, and HBeAg in group 2b were lower than those in group 2a (
P
<
0.05
). Conclusions. Both PEG-IFNα-2a and PEG-IFNα-2b have excellent and stable therapeutic effects on HBeAg-positive CHB, among which PEG-IFNα-2b renders a faster treatment process but higher side effects, which can provide valuable references when choosing a treatment plan for CHB.